Nasal preparation of guanidinoimino quinoline derivatives

ABSTRACT

A nasal preparation comprising a compound represented by the formula:                    
     wherein Ring A is an optionally substituted 5- or 6-membered aromatic heterocyclic ring, Ring B is an optionally substituted 5- or 6-membered aromatic homocyclic or heterocyclic ring, R 1  is a hydrogen atom, a hydroxyl group or a lower alkyl group, and n is 0 or 1, which has an Na—H exchange inhibiting activity, or a salt thereof exhibits excellent bioabsorbability and an Na—H exchange inhibiting activity superior to that of an oral preparation, thus being useful as a prophylactic and/or therapeutic agent for ischemic heart diseases such as myocardial infarct and arrhythmia.

This application is the National Stage of International Application No.PCT/JP00/03559, filed on Jun. 1, 2000.

FIELD OF THE INVENTION

The present invention relates to a nasal preparation which contains anovel aminoguanidine hydrazone derivative and the like. A nasalpreparation according to the present invention has a prophylactic andtherapeutic effect on myocardial infarction and accompanyingdysfunctions, arrhythmia, unstable angina, cardiac hypertrophy,restenosis after PTCA (percutaneous transluminal coronary angioplasty),hypertension and accompanying tissue failures and the like, since itsactive ingredient, i.e., amino guanidine hydrazone derivative, has asodium-proton (Na—H) exchange inhibiting activity.

BACKGROUND OF THE INVENTION

While various pharmaceuticals were developed and employed in clinicalpractice widely, most of them are employed as oral or injectablepreparations. An injectable preparation is employed instead of an oralpreparation, when an active ingredient is poorly absorbed orally due toan instability in a digestive tract, a poor migration through the wallof a digestive tract and a disadvantageous first pass effect, or when anactive ingredient has a digestive tract tissue damaging effect, or whena pharmacological effect should be exerted instantaneously. However,administration via an injection poses a substantial pain to a patientand a substantial inconvenience due to the impossibility of beingperformed by a patient himself, and becomes problematic especially whenthe treatment is prolonged.

A nasal administration is an attractive non-injection method foradministering an agent conveniently. A nasal administration isadvantageous because it can be performed by a patient himself and alsobecause it is scarcely subjected to a metabolism in a liver (first-passeffect) due to a direct introduction of an agent into a systemic bloodcirculation, and also advantageous because it may exhibit a rapidpharmacological effect due to a generally rapid absorption of an agentonce given nasally.

On the other hand, an Na—H exchange inhibitor which is considered tohave an improving effect or a cell protecting effect on a cytopathyunder an ischemic condition (especially on a myocardial cell) is anattractive agent in the field of the treatment of ischemic diseases.

Various acylguanidine derivatives are disclosed as Na—H exchangeinhibitors in JP-A-6-228082, WO96/04241, EP708091 and EP708088.

JP-A-6-509798 discloses a pyrazine derivative represented by theformula:

wherein R¹ is H or a C₁₋₆ alkyl, R² is 1-morpholinyl, an optionallysubstituted C₁₋₆ alkyl and the like, R³, R⁴, R⁵ and R⁴ are same ordifferent and each denotes hydrogen, a C₁₋₆ alkyl or benzyl as an agentwhich has an Na—H exchange inhibiting effect and which may beadministered as a nasal preparation.

JP-A-9-504535 discloses a benzoylguanidine derivative represented by theformula:

wherein A is —C_(m)H_(2m)—NR₄— and the like, R¹ is F, Cl, CF₃, R¹—SO₂—or R¹—NH—SO₂— (in which R¹ is a C₁₋₅ alkyl, halogen- orphenyl-substituted C₁₋₅ alkyl and the like), R₂ is a group representedby the formula:

and R₃, R₄ and R₅ are same or different and each denotes hydrogen or aC₁₋₄ alkyl and the like as an agent which has an Na—H exchangeinhibiting effect and which may be administered as nose drops ifpossible.

JP-A-9-505035 discloses a pyrazine carboxyamide derivative representedby the formula:

wherein A is —C_(m)H_(2m)—NR₄— and the like which is bound via anitrogen atom to a pyrazine carboxyamide system, R₁ is hydrogen,fluorine, chlorine, a C₁₋₄ alkyl and the like, R₂ is a group representedby the formula:

and R₃, R₄ and R₄′ are same or different and each denotes hydrogen or aC₁₋₄ alkyl and the like as an agent which has an Na—H exchangeinhibiting effect and which may be administered as nose drops ifpossible.

WO98/19682 discloses an aminosterol compound represented by the formula:

as an agent which has an Na—H exchange inhibiting effect and which canbe administered to a nasal cavity.

SUMMARY OF THE INVENTION

An objective of the present invention is to provide a nasal preparationwhich exerts an excellent effect as a prophylactic and therapeutic agentfor myocardial infarction and accompanying dysfunctions, arrhythmia,unstable angina, cardiac hypertrophy, restenosis after PTCA,hypertension and accompanying tissue failures and the like and is asufficiently satisfactory pharmaceutical composition when compared withan oral preparation or an injectable preparation.

The present inventors have studied nasal preparations intensively forobtaining a prophylactic and therapeutic agent described above. As aresult, it has been found that a novel aminoguanidine hydrazone compoundrepresented by the formula (I):

wherein Ring A is an optionally substituted 5- or 6-membered aromaticheterocyclic ring, Ring B is an optionally substituted 5- or 6-memberedaromatic homocyclic or heterocyclic ring, R¹ is a hydrogen atom, ahydroxyl group or a lower alkyl group, and n is 0 or 1, or a saltthereof (hereinafter abbreviated as Compound (I)) exhibits an excellentNa—H exchange inhibiting activity (especially NHE-1 selective Na—Hexchange inhibiting activity) as well as an excellent in vivo absorptionvia a nasal mucosa and an excellent migration into a heart, and exertsan unexpectedly excellent pharmacological activity, when used in a nasalpreparation, which is comparable with an oral or injectable preparationand is satisfactory characteristically as a medicine, wherebyestablishing the present invention.

Thus, the present invention relates to:

(1) a nasal preparation comprising a compound represented by the formula(I) or a prodrug thereof;

(2) the nasal preparation as described in the above (1), wherein Ring Ais a 5- or 6-membered nitrogen-containing aromatic heterocyclic ringcontaining 1 or 2 nitrogen atoms optionally substituted by an optionallyhalogenated C₁₋₆ alkyl or an optionally halogenated C₁₋₆ alkoxy, Ring Bis a 5- or 6-membered aromatic homocyclic or heterocyclic ringoptionally containing one heteroatom selected from the group consistingof oxygen, sulfur and nitrogen atoms which is optionally substituted bya halogen atom, an optionally halogenated C₁₋₆ alkyl, a hydroxyl groupor an optionally halogenated C₁₋₆ alkoxy, R¹ is a hydrogen atom or ahydroxyl group, and n is 1;

(3) the nasal preparation as described in the above (1) comprising(±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof;(±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof; or(±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof;

(4) the nasal preparation as described in the above (1) comprising(S)-(−)-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof;(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof; or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof;

(5) the nasal preparation as described in the above (1) which is aprophylactic and therapeutic agent for an ischemic heart disease;

(6) the nasal preparation as described in the above (1), wherein saidischemic heart disease is myocardial infarction, unstable angina orarrhythmia;

(7) the nasal preparation as described in the above (1) which is aprophylactic and therapeutic agent for cardiac insufficiency;

(8)(S)-(−)-7-(5-Fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof;

(9)(S)-(−)-7-(2-Chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof;

(10) a pharmaceutical composition comprising(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof; or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof;

(11) the composition as described in the above (10) which is an Na—Hexchange inhibitor;

(12) the composition as described in the above (10) which is a nasalpreparation;

(13) the composition as described in the above (10) which is aprophylactic and therapeutic agent for an ischemic heart disease;

(14) the composition as described in the above (13), wherein saidischemic heart disease is myocardial infarction, unstable angina orarrhythmia;

(15) the composition as described above in the above (10) which is aprophylactic and therapeutic agent for cardiac insufficiency;

(16) use of(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof; or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof for manufacturing an Na—H exchangeinhibitor; and,

(17) a method for inhibiting an Na—H exchange in mammals comprisingadministering an effective amount of(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof; or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof to said mammals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the change in the serum level of Compound B after the nasaladministration of Formulations 1 to 4 and after the intravenousadministration of the formulation of Comparative 1.

FIG. 2 shows the change in the serum level of Compound B after the nasaladministration of Formulations 5 and 6 and after the intravenousadministration of the formulation of Comparative 1.

In the above formula (I), Ring A denotes an optionally substituted 5- or6-membered aromatic heterocyclic ring.

The aromatic heterocyclic ring in the “optionally substituted 5- or6-membered aromatic heterocyclic ring” represented by A may for examplebe an aromatic heterocyclic ring having as an atom constituting the ringsystem (a ring atom) at least one (preferably 1 to 3, more preferably 1or 2) atom of 1 to 3 (preferably 1 to 2) heteroatoms selected from thegroup consisting of oxygen, sulfur and nitrogen atoms.

The “aromatic heterocyclic ring” may for example be a 5- or 6-memberedaromatic heterocyclic ring such as furan, thiophene, pyrrole, oxazole,isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole,pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like.

Among those listed above, a 5- or 6-membered aromatic heterocyclic ringhaving 1 to 3 (preferably 1 to 2) heteroatoms selected from the groupconsisting of oxygen, sulfur and nitrogen atoms, and typical examples ofRing A are a pyridine ring, a pyridazine ring, a pyrrole ring, apyrazole ring, a furan ring, a thiophene ring, an isoxazole ring, apyrimidine ring (preferably a 5- or 6-membered nitrogen-containingaromatic heterocyclic ring containing 1 or 2 nitrogen atoms such as apyridine ring, a pyridazine ring, a pyrrole ring, a pyrazole ring andthe like, more preferably a 5- or 6-membered nitrogen-containingaromatic heterocyclic ring containing 1 or 2 nitrogen atoms such as apyridine ring, a pyrazole ring, a pyridazine ring and the like), mostpreferably a pyridine ring and the like.

In the above formula (I), Ring B is an optionally substituted 5- or6-membered aromatic homocyclic or heterocyclic ring.

The “optionally substituted 5- or 6-membered aromatic homocyclic ring”represented by B may for example be an optionally substituted benzenering and the like.

The aromatic heterocyclic ring in the “optionally substituted 5- or6-membered aromatic hetercyclic ring” represented by B may for examplebe an aromatic heterocyclic ring having as an atom constituting the ringsystem (a ring atom) at least one (preferably 1 to 3, more preferably 1or 2) atom of 1 to 3 (preferably 1 to 2) heteroatoms selected from thegroup consisting of oxygen, sulfur and nitrogen atoms.

The “aromatic heterocyclic ring” may for example be a 5- or 6-memberedaromatic heterocyclic ring such as furan, thiophene, pyrrole, oxazole,isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole,pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like, witha 5- or 6-membered aromatic heterocyclic ring containing 1 to 3(preferably 1 or 2) heteroatoms selected from the group consisting ofoxygen, sulfur and nitrogen atoms.

Preferred Ring B may typically be a 5- or 6-membered aromatic homocyclicor heterocyclic ring which may contain one heteroatom selected from thegroup consisting of oxygen, sulfur and nitrogen atoms such as a benzenering, a pyrrole ring, a furan ring, a thiophene ring, a pyridine ring(preferably a benzene ring, a furan ring, a thiophene ring and thelike), most preferably a benzene ring and the like.

Ring A and Ring B may be substituted in any possible position which maybe same or different by 1 to 4 (preferably 1 to 2) substituents selectedfrom the group consisting of (1) a halogen atom, (2) a hydroxyl group,(3) a nitro group, (4) a cyano group, (5) an optionally substitutedlower alkyl group, (6) an optionally substituted lower alkenyl group,(7) an optionally substituted lower alkynyl group, (8) an optionallysubstituted lower aralkyl group, (9) an optionally substituted loweralkoxy group, (10) an optionally substituted mercapto group, (11) anoptionally substituted amino group, (12) an optionally esterified oramidated carboxyl group, (13) an optionally substituted sulfonyl group,(14) an optionally substituted acyl group and (15) an optionallysubstituted phenyl group, wherein (16) two adjacent substituents may betaken together to form a divalent hydrocarbon group, or the nitrogenatom in Ring A or Ring B may be oxidized.

When Ring A or Ring B is a nitrogen-containing aromatic heterocylcicring having as a substituent a hydroxyl group such as a 2-oxypyridinering then Ring A or Ring B may denote a nitrogen-containing aromaticheterocyclic ring having an oxo group (which is equivalent structurallyto a nitrogen-containing aromatic heterocyclic ring having as asubstituent a hydroxyl group) such as α-pyridone, and when Ring A orring B is a nitrogen-containing aromatic heterocyclic ring having an oxogroup then the substituent which may be possessed by Ring A or Ring Bmay be present on the nitrogen atom on Ring A or Ring B.

The halogen atom of (1) described above may for example be chlorine,bromine, fluorine, iodine and the like.

The optionally substituted lower alkyl group of (5) described above mayfor example be a C₁₋₆ alkyl group (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl t-butyl, s-butyl, pentyl, hexyl and thelike).

Such lower alkyl group may be substituted in any possible position by 1to 3 same or different substituents selected from the group consistingof a halogen atom (for example, chlorine, bromine, fluorine, iodine andthe like), a hydroxyl group, a nitro group, a cyano group, a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The optionally substituted lower alkenyl group of (6) described abovemay for example be a C₂₋₆ alkenyl group such as vinyl, allyl,isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl and the like.

Such lower alkenyl group may be substituted in any possible position by1 to 3 same or different substituents selected from the group consistingof a halogen atom (for example, chlorine, bromine, fluorine, iodine andthe like), a hydroxyl group, a nitro group, a cyano group, a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The optionally substituted lower alkynyl group of (7) described abovemay for example be a C₂₋₆ alkynyl group such as ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl and the like.

Such lower alkynyl group may be substituted in any possible position by1 to 3 same or different substituents selected from the group consistingof a halogen atom (for example, chlorine, bromine, fluorine, iodine andthe like), a hydroxyl group, a nitro group, a cyano group, a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The optionally substituted lower aralkyl group of (8) described abovemay for example be a C₇₋₁₀ aralkyl group (preferably phenyl-C₁₋₆ alkylgroup) such as benzyl, phenethyl and the like.

Such lower aralkyl group may be substituted in any possible position by1 to 3 same or different substituents selected from the group consistingof a halogen atom (for example, chlorine, bromine, fluorine, iodine andthe like), a hydroxyl group, a nitro group, a cyano group, a lower(C₁₋₆) alkyl group (for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl and the like), ahalogeno-lower (C₁₋₆) alkyl group (for example, CF₃, CF₂CF₃, CH₂F, CHF₂and the like), a lower (C₁₋₆) alkoxy group (for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy,isopentyloxy, neopentyloxy, hexyloxy and the like), a halogeno-lower(C₁₋₆) alkoxy group (for example, CF₃O, CHF₂O and the like) and thelike.

The optionally substituted lower alkoxy group of (9) described above mayfor example be a C₁₋₆ alkoxy group (for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy, pentyloxy,isopentyloxy, neopentyloxy, hexyloxy and the like).

Such lower alkoxy group may be substituted in any possible position by 1to 3 same or different substituents selected from the group consistingof a halogen atom (for example, chlorine, bromine, fluorine, iodine andthe like), a hydroxyl group, a nitro group, a cyano group, a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The optionally substituted mercapto group of (10) described above mayfor example be an optionally substituted C₁₋₆ alkylthio group (forexample, methylthio, ethylthio, propylthio, isopropylthio, butylthio,s-butylthio, t-butylthio, pentylthio, isopentylthio, neopentylthio,hexylthio and the like).

Such C₁₋₆ alkylthio group may be substituted in any possible position by1 to 3 same or different substituents selected from the group consistingof a halogen atom (for example, chlorine, bromine, fluorine, iodine andthe like), a hydroxyl group, a nitro group, a cyano group, a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The optionally substituted amino group of (11) described above may forexample be an amino acid which may optionally be substituted by 1 or 2same or different substituents selected from the group consisting of alower (C₁₋₆) alkyl group (for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl and the like), a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, hexyloxy and thelike), a halogeno-lower (C₁₋₆) alkyl group (for example, CF₃, CF₂CF₃,CH₂F, CHF₂ and the like), a lower (C₃₋₆) cycloalkyl (for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), ahydroxyl group, carbamoyl, phenyl, a phenyl-lower (C₁₋₆) alkyl (forexample, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like),a lower (C₁₋₆) alkyl-carbonyl(alkanoyl) (for example, formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, pivaloyl and the like), a C₃₋₆cycloalkyl-carbonyl (for example, cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and thelike), benzoyl, a phenyl-C₂₋₆ alkanoyl (for example, phenylacetyl,phenylpropionyl and the like), a lower (C₁₋₆) alkoxy-carbonyl (forexample, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl and the like), phenoxycarbonyl, aphenyl-lower (C₁₋₆) alkoxy-carbonyl (for example, benzyloxycarbonyl,phenylethoxycarbonyl and the like), a lower (C₁₋₆) alkylsulfinyl (forexample, methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl,t-butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like), a C₃₋₆cycloalkylsulfinyl (for example, cyclopropylsulfinyl,cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl and thelike), phenylsulfinyl, a lower (C₁₋₆) alkylsulfonyl (for example,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl, s-butylsulfonyl,pentylsulfonyl, hexylsulfonyl and the like), a C₃₋₆ cycloalkylsulfonyl(for example, cyclopropylsulfonyl, cyclobutylsulfonyl,cyclopentylsulfonyl, cyclohexylsulfonyl and the like), a lower (C₁₋₆)alkoxysulfonyl (for example, methoxysulfonyl, ethoxysulfonyl,propoxysulfonyl, isopropoxysulfonyl, butoxysulfonyl, isobutoxysulfonyl,s-butoxtysulfonyl, t-butoxysulfonyl, pentyloxysulfonyl, hexyloxysulfonyland the like) and phenylsulfonyl and the like.

It is also possible that two substituents listed above are takentogether with a nitrogen atom to form a cyclic amino group, such aspyrrolidino, piperidino, morpholino, thiomorpholino and the like.

Each optionally substituted amino group exemplified above may besubstituted in any possible position by 1 to 3 same or differentsubstituents selected from the group consisting of a halogen atom (forexample, chlorine, bromine, fluorine, iodine and the like), a hydroxylgroup, a nitro group, a cyano group, a lower (C₁₋₆) alkyl group (forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl, pentyl, hexyl and the like), a halogeno-lower (C₁₋₆) alkylgroup (for example, CF₃, CF₂CF₃, CH₂F, CHF₂ and the like), a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The optionally esterified or amidated carboxyl group of (12) describedabove includes:

an esterified carboxy group such as a lower (C₁₋₆) alkoxy-carbonyl group(for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl,hexyloxycarbonyl and the like), a C₃₋₆ cycloalkoxy-carbonyl (forexample, cyclopropoxycarbonyl, cyclobutyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like), aphenyl-lower (C₁₋₆) alkoxy-carbonyl (for example, benzyloxycarbonyl,phenylethoxycarbonyl and the like), a nitroxy lower (C₁₋₆)alkoxy-carbonyl (for example, 2-nitroxyethoxycarbonyl,3-nitroxypropoxycarbonyl and the like) and the like;

an amidated carboxyl group such as carbamoyl, N-mono-lower (C₁₋₆)alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,s-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl andthe like), an N,N-di-lower (C₁₋₆) alkyl-carbamoyl (for example,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,N,N-dibutylcarbamoyl and the like), a C₃₋₇ cycloalkyl-carbamoyl (forexample, cyclopropylcarbamoyl, cyclobutylcarbamoyl,cyclopentylcarbamoyl, cyclohexylcarbamoyl and the like), a phenyl-lower(C₁₋₆) alkyl-carbamoyl (for example, benzylcarbamoyl, phenethylcarbamoyland the like), a nitroxy lower (C₁₋₆) alkylamino-carbonyl (for example,2-nitroxyethylcarbamoyl, 3-nitroxypropylcarbamoyl and the like), acyclic aminocarbonyl (for example, morpholinocarbonyl,piperidinocarbonyl, pyrrolidinocarbonyl, thiomorpholinocarbonyl and thelike), anilinocarbonyl and the like.

Each “optionally esterified or amidated carboxyl group” exemplifiedabove may be substituted in any possible position by 1 to 3 same ordifferent substituents selected from the group consisting of a halogenatom (for example, chlorine, bromine, fluorine, iodine and the like), ahydroxyl group, a nitro group, a cyano group, a lower (C₁₋₆) alkyl group(for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, pentyl, hexyl and the like), a halogeno-lower (C₁₋₆)alkyl group (for example, CF₃, CF₂CF₃, CH₂F, CHF₂ and the like), a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The optionally substituted sulfonyl group of (13) described above mayfor example be a lower (C₁₋₆) alkylsulfonyl (for example, a lower (C₁₋₆)alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl and thelike), a C₃₋₆ cycloalkylsulfonyl (for example, cyclopropylsulfonyl,cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and thelike), a phenyl-C₁₋₆ alkylsulfonyl (for example, benzylsulfonyl,phenethylsulfonyl and the like), a lower (C₁₋₆) alkoxysulfonyl (forexample, methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl,isopropoxysulfonyl, butoxysulfonyl, isobutoxysulfonyl, s-butoxysulfonyl,t-butoxysulfonyl, pentyloxysulfonyl, hexyloxysulfonyl and the like), aC₃₋₆ cycloalkyloxysulfonyl (for example, cyclopropoxysulfonyl,cyclobutyloxysulfonyl, cyclopentyloxysulfonyl, cyclohexyloxysulfonyl andthe like), a phenyl-lower (C₁₋₆) alkoxysulfonyl (for example,benzyloxysulfonyl, phenethyloxysulfonyl and the like), sulfamoyl, alower (C₁₋₆) alkylaminosulfonyl (for example, methylaminosulfonyl,ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl,butylaminosulfonyl, isobutylaminosulfonyl, s-butylaminosulfonyl,t-butylaminosulfonyl, pentylaminosulfonyl, hexylaminosulfonyl and thelike), a C₃₋₆ cycloalkylaminosulfonyl (for example,cyclopropylaminosulfonyl, cyclobutylaminosulfonyl,cyclopentylaminosulfonyl, cyclohexylaminosulfonyl and the like), aphenyl-lower (C₁₋₆) alkylaminosulfonyl (for example,benzylaminosulfonyl, phenethylaminosulfonyl and the like), a cyclicaminosulfonyl (for example, morpholinosulfonyl, piperidinosulfonyl,pyrrolidinosulfonyl, thiomorpholinosulfonyl and the like), a nitroxylower (C₁₋₆) alkylamino-sulfonyl (for example,2-nitroxyethylaminosulfonyl, 3-nitroxypropylaminosulfonyl and the like),anilinosulfonyl and the like.

Each “optionally substituted sulfonyl group” exemplified above may besubstituted in any possible position by 1 to 3 same or differentsubstituents selected from the group consisting of a halogen atom (forexample, chlorine, bromine, fluorine, iodine and the like), a hydroxylgroup, a nitro group, a cyano group, a lower (C₁₋₆) alkyl group (forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl, pentyl, hexyl and the like), a halogeno-lower (C₁₋₆) alkylgroup (for example, CF₃, CF₂CF₃, CH₂F, CHF₂ and the like), a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkoxy group (forexample, CF₃O, CHF₂O and the like) and the like.

The lower acyl group of (14) described above may for example be a loweracyl group derived from a carboxylic acid, a sulfinic acid or a sulfonicacid.

The lower acyl group derived from a carboxylic acid may for example be alower (C₁₋₆) alkyl-carbonyl(alkanoyl) (for example, formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, pivaloyl and the like), a C₃₋₆cycloalkyl-carbonyl (for example, cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and thelike), benzoyl and the like.

The lower acyl group derived from a sulfinic acid may for example be alower (C₁₋₆) alkylsulfinyl (for example, methylsulfinyl, ethylsulfinyl,propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl,s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, hexylsulfinyl and thelike), a C₃₋₆ cycloalkylsulfinyl (for example, cyclopropylsulfinyl,cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl and thelike), phenylsulfinyl and the like.

The lower acyl group derived from a sulfonic acid may for example be alower (C₁₋₆) alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, hexylsulfonyl and thelike), a C₃₋₆ cycloalkylsulfonyl (for example, cyclopropylsulfonyl,cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and thelike), phenylsulfonyl and the like.

Each “lower acyl group” exemplified above may be substituted in anypossible position by 1 to 3 same or different substituents selected fromthe group consisting of a halogen atom (for example, chlorine, bromine,fluorine, iodine and the like), a hydroxyl group, a nitro group, a cyanogroup, a lower (C₁₋₆) alkyl group (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl and thelike), a halogeno-lower (C₁₋₆) alkyl group (for example, CF₃, CF₂CF₃,CH₂F, CHF₂ and the like), a lower (C₁₋₆) alkoxy group (for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy,pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like), ahalogeno-lower (C₁₋₆) alkoxy group (for example, CF₃O, CHF₂O and thelike) and the like.

The optionally substituted phenyl group of (15) described above may besubstituted in any possible position by 1 to 3 same or differentsubstituents selected from the group consisting of a halogen atom (forexample, chlorine, bromine, fluorine, iodine and the like), a hydroxylgroup, a nitro group, a cyano group, a lower (C₁₋₆) alkyl group (forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl, pentyl, hexyl and the like), a halogeno-lower (C₁₋₆) alkylgroup (for example, CF₃, CF₂CF₃, CH₂F, CHF₂ and the like), a lower (C16)alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy andthe like), a halogeno-lower (C₁₋₆) alkoxy group (for example, CF₃O,CHF₂O and the like) and the like.

The divalent hydrocarbon group of (16) described above may for examplebe the groups represented by formulae:

—CH═CH—CH═CH—,

—CH═CH—CH₂—CH₂—,

 —CH₂—CH═CH—CH₂—,

—CH═CH—CH₂—,

—(CH₂)_(a)— (wherein a is 3 or 4).

The divalent hydrocarbon group described above taken together with 2ring-constituting atoms in Ring A forms a 5- or 6-membered ring, whichmay be substituted in any possible position by 1 to 3 same or differentsubstituents selected from the group consisting of a lower (C₁₋₆) alkylgroup (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,s-butyl, t-butyl, pentyl, hexyl and the like), a halogen atom (forexample, chlorine, bromine, fluorine, iodine and the like), a lower(C₁₋₆) alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like), a halogeno-lower (C₁₋₆) alkyl group (forexample, CF₃, CF₂CF₃, CH₂F, CHF₂ and the like), a halogeno-lower (C₁₋₆)alkoxy group (for example, CF₃O, CF₂CF₃O, CH₂FO, CHF₂O and the like), alower (C₁₋₆) alkoxy-carbonyl (for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,s-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and thelike), a cyano group, a nitro group, a hydroxyl group and the like.

The substituent on Ring A is preferably be an optionally halogenatedlower (C₁₋₆) alkyl group (preferably methyl), an optionally halogenatedlower (C₁₋₆) alkoxy group (preferably methoxy) and the like, with alower (C₁₋₆) alkyl group (preferably methyl) being more preferred.Preferred Ring A may for example be a ring represented by the formula:

wherein A′ is a 5- or 6-membered aromatic heterocyclic ring which mayfurther have substituents in addition to substituent Ra (preferablypyridine, pyrazole, pyrrole, furan, more preferably pyridine, pyrazoleand the like), Z is an oxygen atom, a sulfur atom or a nitrogen atom, Rais a substituent on Ring A described above (preferably an optionallyhalogenated lower (C₁₋₆) alkyl group, an optionally halogenated lower(C₁₋₆) alkoxy group and the like).

The substituent on Ring B is preferably be a halogen atom (preferablychlorine and the like), an optionally halogenated lower (C₁₋₆) alkyl(preferably methyl and the like), a hydroxyl group, an optionallyhalogenated lower (C₁₋₆) alkoxy group (preferably methoxy and the like),with a halogen atom (preferably chlorine and the like) and a lower(C₁₋₆) alkyl group being preferred especially. Preferred Ring B may forexample be a ring represented by the formula:

wherein B′ is a 5- or 6-membered aromatic homo- or heterocyclic ringwhich may further have substituents in addition to substituent Rb(preferably benzene, thiophene and the like), Y is a carbon atom, anoxygen atom, a sulfur atom or a nitrogen atom, Rb is a hydrogen atom ora substituent on Ring B described above (preferably a halogen atom, anoptionally halogenated lower (C₁₋₆) alkyl group, a hydroxyl group, anoptionally halogenated lower (C₁₋₆) alkoxy group and the like).

In the formula (I) shown above, R¹ is a hydrogen atom, a hydroxyl groupor a lower alkyl group (for example, a lower (C₁₋₆) alkyl group (forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl,t-butyl, pentyl, hexyl and the like), preferably methyl and the like. R¹is preferably a hydrogen atom, a hydroxyl group and a methyl group, morepreferably a hydrogen atom and a hydroxyl atom, especially a hydrogenatom.

In the formula (I) shown above, n is 0 or 1 (preferably 1).

Preferred Compound (I) may for example be a compound represented by theformula:

wherein each symbol is defined as described above or a salt thereof, andmore preferable one is a compound represented by the formula:

wherein each symbol is defined as described above or a salt thereof.

In a preferred example of Compound (I), Ring A is a 5-or 6-memberednitrogen-containing aromatic heterocyclic ring containing 1 or 2nitrogen atoms which may be substituted by an optionally halogenatedC₁₋₆ alkyl or an optionally halogenated C₁₋₆ alkoxy, Ring B is a 5- or6-membered nitrogen-containing aromatic homo- or heterocyclic ringcontaining one heteroatom selected from oxygen, sulfur and nitrogenatoms which may be substituted by a halogen atom, an optionallyhalogenated C₁₋₆ alkyl, a hydroxyl group or an optionally halogenatedC₁₋₆ alkoxy, R¹ is a hydrogen atom or a hydroxyl group, and n is 1.

Typically, preferred Compound (I) is:

(S)-(−)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(S)-(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2-bromophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

7-(3,5-dichlorothiophen-2-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

6-(2,5-dichlorothiophen-3-yl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole,

(±)-7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline,

(±)-7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline,

(±)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnolineor a salt thereof, and, among them, one preferred especially is:

(S)-(−)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(S)-(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2,5-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline,

(±)-7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline,

(±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline,

(±)-7-(5-chloro-2-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnolineor a salt thereof, and, in particular, one preferred is:

(S)-(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof (preferably dimethanesulfonate),

(±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof (preferably dimethanesulfonate),

(±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof,

(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof,

(±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof, and,

(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof, and one employed advantageously is(S)-(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof (preferably dimethanesulfonate), and, when used as anasal preparation, those preferred especially are(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof, and(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof (preferably dimethanesulfonate).

Compound (I) may be present as a prodrug, which means a compound capableof being converted into Compound (I) as a result of an in vivo reactionfor example with an enzyme under a physiological condition, i.e., acompound capable of being converted into Compound (I) as a result of anenzymatic oxidation, reduction, hydrolysis and the like. The prodrug ofCompound (I) may for example a compound formed as a result of acylation,alkylation or phosphorylation of an amino group of Compound (I) (forexample, a compound formed as a result of eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,t-butylation of an amino group of Compound (I)), a compound formed as aresult of acylation, alkylation, phosphorylation and boration of ahydroxyl group of Compound (I) (for example, a compound formed as aresult of acetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fiunarylation, alanylation,dimethylaminomethylcarbonylation of a hydroxyl group of Compound (I)),or a compound formed as a result of esterification and amidation of acarboxyl group of Compound (I) (for example, a compound formed as aresult of ethyl esterification, phenyl esterification, carboxymethylesterification, dimethylaminomethyl esterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethyl esterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification, methyl amidation and the likeof a carboxyl group of Compound (I)). Any of these compounds can beproduced by a method known per se from Compound (I).

The prodrug of Compound (I) may also be a compound which is convertedinto Compound (I) under a physiological condition described in“Development of pharmaceuticals (IYAKUHINNNOKAIHATSU)”, Vol.7, Moleculedesign, pages 163 to 198, published by HIROKAWA SHOTEN in 1990.

Compound (I) and a synthetic intermediate salt thereof may for examplebe a pharmaceutically acceptable salt including an inorganic salt suchas hydrochloride, hydrobromide, sulfate, nitrate and phosphate, anorganic salt such as acetate, tartarate, citrate, fumarate, maleate,toluenesulfonate and methanesulfonate, a salt with an amino acid such asaspartic acid, glutamic acid, pyroglutamic acid, arginine, lysine andornithine, a salt with a metal such as sodium, potassium, calcium andaluminium, a salt with a base such as triethylamine, guanidine,ammonium, hydrazine, quinine, cinchonine and the like.

Compound (I) may be a hydrate or an anhydrous.

When Compound (I) is present as a configuration isomer, diastereomer,conformer and the like, it can be isolated if desired by aseparation/purification method known per se.

Compound (I) shows a geometrical isomerism on the basis of the stericconfiguration in relation to the fused heterocyclic ring containing RingA in a hydrazone structure moiety, and can be present as an E or Zisomer as well as a mixture thereof. In addition, it also shows ageometrical isomerism on the basis of the double bond of a guanidinogroup when R¹ denotes a hydroxyl group or a lower alkyl group, and canbe present as an E or Z isomer as well as a mixture thereof. Thecompound according to the present invention encompasses the followingindividual isomers and mixtures thereof.

Compound (I) also shows an optical isomerism on the basis of anasymmetric carbon atom present for example in the moiety where Ring B issubstituted, and can be present, with regard to each asymmetric carbonatom, as an R or S isomer as well as a mixture thereof. These isomerscan be separated to individual R and S forms by ordinary opticalresolution method, and the respective optical isomers and racemates arealso included in the invention. For example, the compound according tothe present invention encompasses the following individual opticalisomers and mixtures thereof.

In the present invention, a starting compound for Compound (I) or asynthetic intermediate or a salt thereof may sometimes be abbreviated asCompound (I) or a synthetic intermediate by omitting the expression “ora salt thereof”.

Compound (I) is equivalent structurally to Compound (Ia) and Compound(Ib).

Compound (I) can be synthesized by a method in accordance with thosedescribed for example in JP-A-7-309837, Japanese Patent ApplicationNo.9-224945 (JP-A-10-114753), Japanese Patent Application No.9-224946(JP-A-10-114744) and the like, or can be synthesized also by reacting acompound represented by the formula (II):

wherein symbols are defined as described above or a salt thereof with anaminoguanidine compound represented by Formula (III): H₂N—N═C(NH₂)(NHR₁) wherein symbols are defined as described above or a salt thereof.

Compound (III) is employed usually in an amount of about 1 mole to about2 moles per 1 mole of Compound (II). This reaction can be promoted ifnecessary by adding an about 1/10- to about 10-fold molar amount oftriethylamine, pyrrolidine, sodium acetate, borontrifluoride/diethylether, hydrochloric acid, sulfuric acid,p-toluenesulfonic acid and the like as a catalyst.

For example, this condensation reaction can be performed in an inertsolvent such as methanol, ethanol, propanol, isopropanol, n-butanol,tetrahydrofuran, diethylether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetic acid,pyridine, water and the like, as well as a mixture thereof. The reactiontemperature is within the range from about 0° C. to about 180° C.

Compound (II) and Compound (III) employed as starting materials can beproduced by or in accordance with known methods, and can be produced forexample by a method shown in Scheme I or a method described below inReference Example.

In each formula in Scheme I shown above, R² to R¹⁹ and R²² to R²⁴ arethe substituents on Ring A and M¹ to M⁶ are leaving groups.

Each step is detailed below.

(Step 1)

After reacting Compound (XIII) with Compound (XIV), the hydroxyl groupis oxidized to effect a cyclization, whereby producing the ketonecompound (IV). If necessary, the cyclization product is reacted withCompound (XV) in the presence of a base to introduce Substituent R⁴ intothe ketone compound, whereby producing Compound (IV).

This condensation reaction is performed in an inert solvent such astetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol,hexane, toluene, benzene, dichloromethane, acetic acid or a mixturethereof at a temperature within the range from about 0° C. to about 130°C. The reaction time ranges from about 1 hour to about 100 hours.Compound (XIV) is employed in an amount usually of about 1 to about 2moles per 1 mole of Compound (XIII). The reaction can be promoted forexample by adding a molecular sieve.

Subsequent oxidation, cyclization or dehydration may be effected in aprocedure known per se for example by a method in which an equimolar orabout 2-fold molar amount of an aromatic halide is employed as anoxidizing agent in the presence of about 0.1 to about 20% by moles of atransition metal catalyst and one equivalent to about 2-fold molaramount of a base in an inert solvent such as tetrahydrofuran,dimethoxyethane, dimethylformamide, N-methylpyrrolidone, hexane,toluene, benzene, dichloromethane, chloroform or a mixture thereof at atemperature within the range from about 50° C. to about 200° C. Thereaction time ranges from about 1 hour to about 50 hours. The aromatichalide employed as the oxidizing agent may for example be bromobenzene,bromomesitylene, o-bromotoluene and the like. The transition metalcatalyst may for example be nickel, palladium, platinum, ruthenium, andthe reaction can be promoted by using a palladium catalyst such astetrakis(triphenylphosphine) palladium. As the base, potassium carbonateand sodium hydride can be exemplified. This reaction is performed forexample under an inert gas atmosphere (for example, nitrogen, argon).

The reaction with Compound (XV) is performed in an inert solvent such astetrahydrofuran, dimethoxyethane, dimethylformamide,N-methylpyrrolidone, hexane, toluene, benzene, dichloromethane,chloroform or a mixture thereof at a temperature within the range fromabout 0° C. to about 150° C. The reaction time ranges from about 1 hourto 5 hours. The base which can be employed is triethylamine, lithiumhydride, sodium hydride, sodium methoxide, sodium ethoxide, potassiumt-butoxide and the like. Compound (XV) is employed in an amount usuallyof about 1 to about 2 moles per 1 mole of Compound (XIII).

(Step 2)

Compound (XIII) is reacted with an aminating agent to form an enaminederivative, which is then reacted with Compound (XVI) (wherein R²⁰ is—CH₂COCH₃, —C═CH, —CH₂CH(OMe)₂ and the like) to form the ketone compound(V). Alternatively, Compound (XIII) is reacted with Compound (XVI) ifnecessary in the presence of an aminating agent to produce the ketonecompound (V) without isolating an enamine derivative.

The amination is performed in the presence of an aminating agent such asammonium acetate in an inert solvent such as methanol, ethanol, benzene,toluene, chloroform, dichloromethane, 1,2-dichloroethane,tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamideand the like as well as a mixture thereof at a temperature within therange from about 0° C. to about 150° C. The reaction time ranges fromabout 1 hour to about 100 hours. The aminating agent is employed in anamount usually of about 1 to about 10 moles per 1 mole of Compound(XIII).

The condensation and cyclization reaction is performed in an inertsolvent such as methanol, ethanol, benzene, toluene, chloroform,dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether,hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide and the likeas well as a mixture thereof at a temperature within the range fromabout 0° C. to about 150° C. The reaction time ranges from about 1 hourto about 50 hours. Compound (XVI) is employed in an amount usually ofabout 1 to about 5 moles per 1 mole of Compound (XIII).

Also when the enamine derivative is not isolated, the reaction isperformed similarly in the presence of the aminating agent such asammonium acetate.

(Step 3)

After reacting Compound (XIII) with Compound (XVII), cyclization andoxidation are performed to produce the ketone compound (V).

This condensation reaction is performed in an inert solvent such astetrahydrofuran, diethylether, dimethoxyethane, methanol, ethanol,hexane, toluene, benzene, dichloromethane or a mixture thereof at atemperature within the range from about 0° C. to about 130° C. Thereaction time ranges from about 1 hour to about 100 hours. Compound(XVII) is employed in an amount usually of about 1 to about 2 moles per1 mole of Compound (XIII).

Subsequent cyclization and oxidation are performed without any solventor in an inert solvent such as diphenyl ether, tetrahydrofuran,dimethylformamide, dimethylsulfoxide, xylene, toluene or a mixturethereof in an air (or under an oxygen atmosphere) at room temperature toabout 300° C. The reaction time ranges from about 1 hour to about 10hours.

(Step 4)

After reacting Compound (XIII) with the aminating agent, the reactionwith Compound (XVIII) followed by cyclization results in the ketonecompound (VI).

The amination is performed similarly to Step 2.

The subsequent condensation reaction is performed in an inert solventsuch as methanol, ethanol, benzene, toluene, chloroform,dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether,hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide and the likeas well as a mixture thereof at a temperature within the range fromabout 0° C. to about 100° C. The reaction time ranges from about 1 hourto about 50 hours. Compound (XVIII) is employed in an amount usually ofabout 1 to about 2 moles per 1 mole of Compound (XIII).

The subsequent cyclization reaction is performed without any solvent orin an inert solvent such as tetrahydrofuran, diphenyl ether,dimethoxyethane, methanol, ethanol, dichloromethane, chloroform, hexane,benzene, toluene and the like or a mixture thereof at about 50° C. toabout 300° C. The reaction time ranges from about 10 minutes to about 5hours.

(Step 5)

By halogenating Compound (VI) produced in Step 4, the ketone compound(VII) (wherein X is a halogen atom) can be produced.

The halogenation can be performed in a procedure known per se forexample by a method in which phosphorus oxychloride is employed as ahalogenating agent in an about 1- to about 20-fold amount without anysolvent or in an inert solvent such as tetrahydrofuran, dimethoxyethane,hexane, toluene, benzene, dichloromethane, chloroform or a mixturethereof at a temperature of about 0° C. to about 150° C. The reactiontime ranges from about 30 minutes to about 10 hours. The reaction can bepromoted for example by adding dimethylformamide.

(Step 6)

By reacting Compound (VII) produced in Step 5 with Compound (XIX), theketone compound (VIII) can be produced.

The reaction is performed in an inert solvent such as tetrahydrofuran,diethyl ether, dimethoxyethane, methanol, ethanol, hexane, toluene,benzene, dichloromethane, chloroform, dimethylformamide,dimethylsulfoxide or a mixture thereof at a temperature within the rangefrom about 0° C. to about 150° C. The reaction time ranges from about 30minutes to about 50 hours. While Compound (XIX) is employed usually inan amount of about 1 to about 2 moles per 1 mole of Compound (VII), itcan be employed also as a solvent. If necessary, a base such as lithiumhydride, sodium hydride, sodium methoxide, sodium ethoxide and potassiumt-butoxide can be employed.

(Step 7)

After reacting Compound (XIII) with Compound (XX), Compound (XXI)(wherein A-B is an optionally substituted hydrazine, hydroxylamine andthe like) is reacted and cyclized to produce the ketone compound (IX) or(IX′).

The condensation reaction is performed by a method known per se in thepresence of a condensing agent such as DDC and WSC in an inert solventsuch as tetrahydrofuran, diethylether, dimethoxyethane,dimethylformamide, dimethylsulfoxide, hexane, toluene, benzene,dichloromethane, chloroform, ethyl acetate or a mixture thereof, whileserving as a base, at a temperature within the range from about 0° C. toabout 150° C. The reaction time ranges from about 1 hour to about 50hours. Compound (XX) is employed usually in an amount of about 1 to 3moles per 1 mole of Compound (XIII).

The subsequent cyclization reaction is performed in an inert solventsuch as tetrahydrofuran, diphenyl ether, dimethoxyethane, methanol,ethanol, hexane, toluene, benzene, dichloromethane, chloroform,dimethylformamide, dimethylsulfoxide or a mixture thereof at atemperature within the range from about 0° C. to about 150° C. Thereaction time ranges from about 1 hour to about 50 hours. Compound (XXI)is employed usually in an amount of about 1 to 2 moles per 1 mole ofCompound (XIII).

(Step 8)

After reacting Compound (XIII) with Compound (XXII), Compound (XXIII) isreacted and cyclized to produce the ketone compound (X).

The condensation reaction is performed by a method similar to thatemployed in the condensation in Step 7.

The subsequent cyclization reaction is performed in an inert solventsuch as tetrahydrofuran, diphenyl ether, dimethoxyethane, methanol,ethanol, hexane, benzene, toluene, dichloromethane, chloroform,dimethylformamide, dimethylsulfoxide or a mixture thereof at atemperature within the range from about 0° C. to about 150° C. Thereaction time ranges from about 1 hour to about 100 hours. This reactioncan be promoted when the product of the first condensation reaction isreacted with an amine to form an enamine derivative which is thenreacted with Compound (XXIII).

(Step 9)

After reacting Compound (XIII) with Compound (XXIV), a cyclization isperformed to produce the ketone compound (XI).

This condensation reaction is performed in an inert solvent such astetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol,hexane, toluene, benzene, dichloromethane, chloroform,dimethylformamide, dimethylsulfoxide or a mixture thereof in thepresence of a base at a temperature within the range from about 0° C. toabout 100° C. The reaction time ranges from about 30 minutes to about 20hours. The base which can be employed may for example be lithiumhydride, sodium hydride, sodium methoxide, sodium ethoxide, potassiumt-butoxide and the like. Compound (XXIV) is employed usually in anamount of about 1 to 2 moles per 1 mole of Compound (XIII).

The subsequent cyclization reaction is performed without any solvent orin an inert solvent such as tetrahydrofuran, diphenyl ether,dimethoxyethane, methanol, ethanol, dimethylformamide,dimethylsulfoxide, xylene, toluene, dichloromethane, chloroform and thelike or a mixture thereof at room temperature to about 300° C. Thereaction time ranges from about 1 hour to about 50 hours.

(Step 10)

After Compound (XIII) is halogenated, it is reacted for example withNa₂S and the resultant product is then reacted with Compound (XXV) toeffect cyclization, whereby producing the ketone compound (XII).

The halogenation can be effected in a procedure known per se for exampleby a method in which phosphorus trichloride is employed as ahalogenating agent in an about 1/3- to 5-fold molar amount without anysolvent or in an inert solvent such as tetrahydrofuran, dimethoxyethane,hexane, toluene, benzene, dichloromethane, chloroform or a mixturethereof at a temperature within the range from about 0° C. to about 150°C. The reaction time ranges from about 30 minutes to about 10 hours.

The reaction for example with Na₂S is performed in an inert solvent suchas water, tetrahydrofuran, diethyl ether, dimethoxyethane, methanol,ethanol, hexane, toluene, benzene, dichloromethane, chloroform or amixture thereof at a temperature within the range from about 0° C. toabout 100° C. The reaction time ranges from about 30 minutes to about 10hours.

The condensation reaction is performed in an inert solvent such as suchas tetrahydrofuran, diethyl ether, dimethoxyethane, methanol, ethanol,hexane, toluene, benzene, dichloromethane, chloroform,dimethylformamide, dimethylsulfoxide or a mixture thereof at atemperature within the range from about 0° C. to about 100° C. Thereaction time ranges from about 30 minutes to about 20 hours. The basewhich can be employed may for example be lithium hydride, sodiumhydride, sodium methoxide, sodium ethoxide, potassium t-butoxide and thelike. Compound (XXV) is employed usually in an amount of about 1 to 2moles per 1 mole of Compound (XIII).

The subsequent cyclization reaction is performed without any solvent orin an inert solvent such as tetrahydrofuran, diphenyl ether,dimethoxyethane, methanol, ethanol, dimethylformamide,dimethylsulfoxide, xylene, toluene, dichloromethane, chloroform and thelike or a mixture thereof at room temperature to about 300° C. Thereaction time ranges from about 1 hour to about 100 hours.

(Step 11)

After Compound (XIII) is reacted with Compound (XXVII) (wherein R21 isan optionally substituted phenyl such as phenyl, 4-methylphenyl,4-methoxyphenyl and the like) to form a hydrazide derivative, it isreacted with Compound (XXVIII) in the presence of a base to produce theketone compound (XXVI).

The reaction with Compound (XXVII) is performed in an inert solvent suchas methanol, ethanol, toluene, benzene, dichloromethane, chloroform,1,2-dichloromethane, tetrahydrofuran, diethylether, hexane, ethylacetate, dimethylformamide, or a mixture thereof at a temperature withinthe range from about 0° C. to about 150° C. The reaction time rangesfrom about 1 hour to about 100 hours. The aminating agent is usedusually in an amount of about 1 to about 10 moles per 1 mole of Compound(XIII).

The reaction with Compound (XXVIII) and cyclization are performed in aninert solvent such as methanol, ethanol, toluene, benzene,dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran,diethyl ether, hexane, ethyl acetate, dimethylformamide,dimethylsulfoxide, or a mixture thereof at a temperature within therange from about 0° C. to about 150° C. The reaction time ranges fromabout 1 hour to 50 hours. The base which can be employed is potassiumcarbonate, lithium hydride, sodium hydride, sodium methoxide, sodiumethoxide, potassium t-butoxide and the like. Compound (XXVIII) isemployed in an amount usually of about 1 to about 5 moles per 1 mole ofCompound (XIII).

The ketone compound obtained in any of Steps 1 to 11 can be employed inthe next step without isolation or purification.

When the compound has a carbonyl group, an amino group, a hydroxyl groupor a carboxyl group in any of the production methods described above, anordinary protective group may previously be introduced into the compoundby a method known per se and it may be removed if necessary after thereaction to obtain an intended product.

A protective group for the carbonyl group employed here may for examplebe an optionally substituted cyclic or acyclic acetal or ketal, anoptionally substituted cyclic or acyclic dithioacetal or dithioketal.

A protective group for the amino group employed here may for example bea lower (C₁₋₆) alkyl-carbonyl (for example, formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, pivaloyl and the like) and benzoyl.

A protective group for the hydroxyl group may for example bemethoxydimethylmethyl, trimethylsilyl, t-butyldimethylsilyl,trimethylsilylethoxymethyl, (SEM), methoxymethyl, benzyloxymethyl andtetrahydropyranyl (THP).

A protective group for the carboxyl group may for example be a lower(C₁₋₆) alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, s-butyl, t-butyl, pentyl, hexyl and the like), a C₇₋₁₂ aralkyl(for example, benzyl, phenethyl, 4-phenylpropyl, 4-phenylbutyl,1-naphthylmethyl and the like). The carboxyl group may be protected alsoas being converted into a 2-oxazoline ring.

While a method for introducing and cleaving a protective group may be inaccordance (with a method known per se (for example, a method describedin Protective Groups in Organic Chemistry, J. F. W. McOmie et al.,Plenum Press), a cleavage may also be accomplished using acids, base,reductions, ultraviolet light, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateand the like.

Among the starting compounds and the synthetic intermediates forCompound (I) described above, a basic compound can be converted into asalt using an acid in accordance with a standard method. A suitable acidfor this reaction is preferably an acid which gives a pharmaceuticallyacceptable salt. Those which can be exemplified are inorganic acids suchas hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,nitric acid and sulfamic acid as well as organic acids such as aceticacid, tartaric acid, citric acid, fumaric acid, maleic acid,p-toluenesulfonic acid, methanesulfonic acid, glutamic acid andpyroglutamic acid. When a resultant compound is a salt, it may beconverted into a free base in accordance with a standard method.

Among the starting compounds and the synthetic intermediates forCompound (I), a compound having an acidic group such as —COOH can beconverted into a salt in accordance with a standard method. Such salt ispreferably a salt with an alkaline metal, an alkaline earth metal,ammonium, a substituted ammonium and the like, more typically, a saltwith sodium, potassium, lithium, calcium, magnesium, aluminium, zinc,ammonium tri-C₁₋₆ alkylammonium (for example, trimethylammonium,triethylammonium and the like), triethanolammonium and the like.

Each reaction described above is conducted usually from equimolaramounts of respective starting materials for a period usually of 1 to 24hours, unless otherwise specified.

Compound (I) or a starting material therefor thus obtained can beisolated from the reaction mixture by an ordinary separating andpurifying procedure, such as extraction, concentration, neutralization,filtration, crystallization, recrystallization, column (or thin layer)chromatography and the like.

Compound (I) has an excellent Na—H exchange inhibitory effect and a lowtoxicity and a high stability.

The nasal preparation according to the present invention can beformulated using Compound (I) as an active ingredient by a method knownper se, if appropriate in a mixture with an appropriate amount of apharmaceutically acceptable carrier.

A pharmaceutically acceptable carrier may for example be a conventionalorganic or inorganic substance as an ingredient of a pharmaceuticalpreparation, such as excipient, lubricant, binder, disintegrant,vehicle, solubilizer, suspending agent, isotonicity, buffer, analgesicagent and the like. If necessary, additives such as preservative,antioxidant, colorant, sweetener, adsorbent, wetting agent and the likemay also be added.

The excipient may for example be lactose, sugar, D-mannitol, starch,corn starch, crystalline cellulose, light silicic anhydride and thelike.

The lubricant may for example be magnesium stearate, calcium stearate,talc, colloidal silica and the like.

The binder may for example be crystalline cellulose, sugar, D-mannitol,dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose,sodium carboxymethyl cellulose and the like.

The disintegrant may for example be starch, carboxymethyl cellulose,calcium carboxymethyl cellulose, sodium *CROSCARMELOSE*, sodiumcarboxymethyl starch, L-hydroxypropyl cellulose and the like.

The vehicle may for example be water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil and the like.

The solubilizer may for example be polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate and thelike.

The suspending agent may for example be a surfactant such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerinmonostearate and the like; a hydrophilic polymer such as polyvinylalcohol, polyvinyl pyrrolidone, sodium carboxymehtyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose and the like.

The isotonicity may for example be glucose, D-sorbitol, sodium chloride,glycerin, D-mannitol and the like.

The buffer may for example be a buffer solution of phosphates, acetates,carbonates, citrates and the like.

The analgesic may for example be benzyl alcohol and the like.

The preservative may for example be p-oxybenzoate, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and thelike.

The antioxidant may for example be sulfites and ascorbates.

More typically, the nasal preparation according to the present inventioncan be formulated as a powder by dispersing, adhering and binding aneffective amount of Compound (I) uniformly into a physiologicallyacceptable particulate carrier whose mean particle size is 250 μm orless. Specifically, Compound (I) is mixed with the carrier. This mixingprocedure may also be performed with exerting a pressure or a sheerstress as is often the case with a mortar.

In the present invention, the carrier into which Compound (I) isdispersed, adhered and bound is a di- or higher polyvalent metalcompound, such as aluminum compounds, calcium compounds, magnesiumcompounds, silicon compounds, iron compounds, zinc compounds and thelike, which are particulate compounds employed as pharmacologicallyacceptable carriers from a pharmaceutical point of view.

The calcium compound employed here as a di- or higher polyvalent metalcompound may for example be calcium carbonate, apatite, hydroxyapatite,disodium calcium edetate, calcium chloride, calcium citrate, calciumgluconate, calcium glycerophosphate, calcium silicate, calciumhydroxide, calcium oxide, calcium stearate, calcium t-phosphate, calciumlactate, calcium pantothenate, calcium palmitate, calciumD-pantothenate, calcium alginate, calcium oleate, anhydrous calciumphosphate, calcium hydrogen phosphate, calcium hydrogen phosphate,calcium dihydrogen phosphate, calcium sulfate, calcium acetate, calciumsaccharate, calcium p-aminosalicylate, biological lime compound and thelike.

The aluminum compound may for example be chlorohydroxyaluminium, driedaluminium hydroxide gel, light alumilnium oxide, synthetic aluminiumsilicate, colloidal hydrated aluminium silicate, aluminium hydroxide,magnesium aluminium hydroxide, aluminium hydroxide gel, aluminiumsulfate, calcium aluminium sulfate, dihydroxyaluminium acetate,aluminium stearate, aluminium monostearate, naturally-occurringaluminium silicate and the like.

The magnesium compound may for example be magnesium carbonate, magnesiumchloride, magnesium oxide, magnesium hydroxide, magnesium L-aspartate,magnesium gluconate, magnesium sulfate, magnesium aluminate silicate,magnesium aluminate metasilicate, magnesium silicate, magnesiumstearate, magnesium sodium silicate, synthetic magnesium sodium silicateand the like.

Examples of the silicon compound include hydrated silicon dioxide,silicon dioxide, light silicic anhydride, synthetic hydrotalcite,diatomaceous earth and the like, and examples of the iron compoundinclude iron sulfate and the like. Examples of the zinc compound includezinc chloride, zinc oxide, zinc sulfate, zinc stearate and the like.

Each of the polyvalent metal compound may be employed alone or incombination with each other. The polyvalent compound has a mean particlesize of about 250 μm or less, preferably about 100 μm or less, morepreferably about 30 to about 60 μm.

Among these polyvalent metal compounds described above, a calciumcompound, especially calcium carbonate, is employed preferably.

On the other hand, preferably, Compound (I) is divided particles as fineas possible.

When the nasal preparation according to the present invention isformulated as a powder, the amount of Compound (I) may for example beabout 0.01 to about 100%, preferably about 0.1 to about 50%, morepreferably about 1 to about 20% based on 100% by weight of theformulation. The amount of a carrier as an ingredient of the nasalpreparation according to the present invention may for example be about0 to about 99.99%, preferably about 50 to about 99.9%, more preferablyabout 80 to about 99% based on 100% by weight of the preparation.

When the nasal preparation according to the present invention isformulated as a liquid preparation, it can be produced by dissolving,suspending or emulsifying Compound (I) in water, physiological salineand the like to obtain a predetermined volume if necessary incombination with vehicle, solubilizing agent, suspending agent,isotonicity, buffering agent, analgesic and the like. In such case, theconcentration of Compound (I) in a solution may for example be about 2mg/ml to about 5 g/ml, preferably about 50 mg/ml to about 500 mg/ml.Since the pH of the solution after dissolution may become 3 or lower, itis preferable to use the solution after adjusting its pH within therange from pH 3 to pH 8, more preferably pH 4 to pH 7, by adding asuitable buffering agent (for example, phosphate, citrate and the like)to suppress any irritating effects on the nasal mucosa uponadministration. While the compound may sometimes deposit partially toform a suspension, a suitable suspending agent (for example, sodiumcarboxymethyl cellulose, hydroxypropyl cellulose and the like) may beadded. Sodium alginate, sodium hyaluronate or hydroxypropyl cellulosemay also be added to give a viscosity, whereby prolonging a residentialtime.

While the amount of Compound (I) in the preparation according to thepresent invention may be selected depending on the activity of Compound(I) and the amount required for a treatment, it is preferably adjustedto be a usual dose or greater in a unit dosage form in view of the factthat the bioavailability is not 100% and thus the compound onceadministered is not always absorbed entirely. Also when theadministration is performed several times repetitively from an identicalcontainer in the form for example of a liquid or an aerosol, the singledosage is preferably adjusted usually to be a dose or greater. Anattention should be paid also to the difference in the dosage betweenthe kinds or the body weights of warm-blooded animals such as humanbeing, livestocks and the like.

While the preparation according to the present invention, when stillbeing not opened, is stored at ambient temperature or in a cool place,it is stored preferably in a cool place. The ambient temperature or thecool place means those defined under Japanese pharmacopoeia. When theadministration is performed several times repetitively from an identicalcontainer, a certain means for preventing any contamination uponadministration, for example a means for preventing a countercurrent of abody fluid into the container, is desired, and a storage in a cool placeis preferred. Also in order to prevent any growth of an undesirableorganism in a container, a pharmaceutically acceptable preservative orantibacterial agent may be added.

The nasal preparation containing Compound (I) having an excellent Na—Hexchange inhibitory activity thus obtained has low toxicity andexcellent stability, because of which it can be administered safely as amedicine and exhibits an excellent Na—H exchange inhibitory activitywhich leads to a cell dysfunction improving effect and a cell protectingeffect (especially on myocardial cell) in animals, especially in mammals(for example human, monkey, pig, dog, cat, rabbit, guinea pig, rat,mouse and the like), and thus is useful as a prophylactic or therapeuticagent for ischemic diseases (for example, myocardial infarction andaccompanying dysfunctions, unstable angina and the like), restenosisafter PTCA, arrhythmia, cardiac insufficiency, cardiac hypertrophy,hypertension and accompanying tissue failures, ischemic cerebraldiseases (for example, cerebral disorders accompanying to cerebralinfarction, cerebral hemorrhage, subarachnoid hemorrhage and the like)(preferably as a prophylactic or therapeutic agent against ischemicdiseases such as myocardial infarction and accompanying dysfunctions,unstable angina and the like, restenosis after PTCA, arrhythmia, cardiacinsufficiency, cardiac hypertrophy, more preferably as a prophylactic ortherapeutic agent against ischemic diseases such as myocardialinfarction, as a prophylactic or therapeutic agent against cardiacinsufficiency). The concept of the prophylaxis of a cardiacinsufficiency means here to include a treatment after a myocardialinfarction, while the concept of the prophylaxis of a cardiacinsufficiency means to include a prevention of the advancement or theexacerbation of the cardiac insufficiency.

While the dose of the nasal preparation according to the presentinvention may vary depending on the subject and the condition to betreated, a patient having a myocardial infarction (adult weighing about60 kg) receives usually as a single dose about 0.005 to about 10 mg/kg,preferably about 0.01 to about 5 mg/kg, more preferably about 0.2 toabout 3 mg/kg (about 0.3 to about 600 mg/adult, preferably about 0.6 toabout 300 mg/adult, more preferably about 12 to about 180 mg/adult) asCompound (I), which is given preferably about one to about three times aday depending on the condition and the like. An acute onset of adisease, such as an acute state after the onset of a myocardialinfarction, may be treated with a higher dose especially at a higherfrequency, for example 4 times a day.

When the nasal preparation according to the present invention isformulated as a powder, a single dose of a powder obtained as describedabove is filled in a conventional capsule (for example, gelatin capsuleNo.2, hydroxypropyl cellulose capsule No.2 and the like), and may beadministered nasally using a customary nasal powder spray container,such as Bubblizer (TEIJIN), Insufflator (PHISONS) or Jetlizer(UNICIAJEX) and the like. In such case, the dose of a powder formulationto a human ranges from about 1 to about 300 mg, preferably about 10 toabout 150 mg, more preferably about 30 to about 100 mg.

When a liquid formulation is employed, Compound (I) dissolved forexample in physiological saline or a vacuum-dried or freeze-driedCompound (I)-containing formulation dissolved in water or physiologicalsaline may be infused by a sprayer or a suitable infuser. In such case,the volume of such solution to a human ranges from about 1 to about 200μl, preferably about 10 to about 100 μl, more preferably about 30 toabout 80 μl.

An active ingredient contained in the nasal preparation according to thepresent invention may not only be Compound (I) described above but alsobe any of the following Na—H inhibiting compound or NSI-1436 in anappropriate amount.

Compound Described in DE-19712636 TY-12533

An agent which can be administered in combination with each Na—Hinhibiting compound listed above is exemplified below and may beadministered orally or parenterally (for example, nasally, via injectionor suppository), and each may be incorporated into a single formulationor may individually be formulated together with a pharmaceuticallyacceptable carrier, excipient, binder or diluent and then administeredseparately or simultaneously. When an agent is formulated individually,such individually formulated agents may be mixed just before use forexample using a diluent, or may be administered simultaneously or at acertain interval to an identical subject.

Examples of agents exhibiting synergistic effects when combined withNa—H inhibiting compounds:

Thrombolytic agent (for example, urokinase, alteplase);

Antiplatelet agent (for example, aspirin, ozagrel sodium, ticlopidineHydrochloride);

Anticoagulant (for example, heparin, warfarin, argatroban);

Cardiotonic agent (for example, cathecolamine formulation such asdopamine hydrochloride and dobutamine hydrochloride or digitalisformulation such as digoxin);

Coronary dilator (nitrite formulation such as nitroglycerin, isosorbidenitrate and nicorandil, Ca antagonist such as nifedipine as well asdipyridamole);

Restenosis preventing agent (such as tranilast);

Hyperlipidemia treating agent (for example, clofibrate, probucol,cerivastatin Sodium);

Antiarrhythmic agent (for example, Class I antiarrhythmic agent such asdisopyramide, lidocaine and procaineamide hydrochloride, Class IIIantiarrhythmic agent such as amiodarone hydrochloride and sotalolhydrochloride, β-blocker such as propranolol hydrochloride or Caantagonist such as verapamil hydrochloride);

Hypotensive agent (for example, angiotensine converting enzyme inhibitorsuch as captopril, enalapril maleate and delapril, angiotensine receptorantagonist such as candesartan cilexetil and potassium losartan,diuretic such as furosemide and spironolactone, Ca antagonist such asamlodipine, manidipine hydrochloride and diltiazem hydrochloride,β-blocker such as atenolol and metoprol or α-blocker such as prazosin);and the like.

Since each of the novel optically active forms encompassed by Compound(I), namely,(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof as well as(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof has an excellent Na—H exchange inhibitory activity,low toxicity and high stability, it can be given as it is or incombination with an appropriate amount of a pharmaceutically acceptablecarrier, excipient or diluent in the form of a pharmaceuticalcomposition such as powder, granule, tablet, capsule (including softcapsule and microcapsule), liquid formulation, injection formulation andsuppository safely via an oral or parenteral administration route, witha parenteral administration (including sublingual formulation) beingpreferred and a nasal preparation being beneficial particularly.

Such pharmaceutical composition exhibits an excellent Na—H exchangeinhibitory activity which leads to a cell dysfunction improving effectand a cell protecting effect (especially on myocardial cell) in animals,especially in mammals (for example human, monkey, pig, dog, cat, rabbit,guinea pig, rat, mouse and the like), and thus is useful as aprophylactic or therapeutic agent for ischemic diseases (for example,myocardial infarction and accompanying dysfunctions, unstable angina andthe like), restenosis after PTCA, arrhythmia, cardiac insufficiency,cardiac hypertrophy, hypertension and accompanying tissue failures,ischemic cerebral diseases (for example, cerebral disorders accompanyingto cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage andthe like) (preferably as a prophylactic or therapeutic agent againstischemic diseases such as myocardial infarction and accompanyingdysfunctions, unstable angina and the like, restenosis after PTCA,arrhythmia, cardiac insufficiency, cardiac hypertrophy, more preferablyas a prophylactic or therapeutic agent against ischemic diseases such asmyocardial infarction, as a prophylactic or therapeutic agent againstcardiac insufficiency). The concept of the prophylaxis of a cardiacinsufficiency means here to include a treatment after a myocardialinfarction, while the concept of the prophylaxis of a cardiacinsufficiency means to include a prevention of the advancement or theexacerbation of the cardiac insufficiency.

Such pharmaceutical composition can be formulated in accordance with amethod known per se, and the amount of(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof contained in the pharmaceutical composition is about0.01 to about 20% (w/w).

A parenteral administration of the pharmaceutical composition accordingto the present invention includes subcutaneous, intravenous,intramuscular and intraperitoneal injections as well as drip infusions.An injectable preparation such as an aseptic aqueous or oily suspensionfor injection can be prepared using a suitable dispersing, wetting orsuspending agent by a method known in the art. An aseptic injectablepreparation may be an aseptic injectable solution or a suspension in anon-toxic parenterally-applicable diluent or a solvent such as anaqueous solution. A vehicle which can be employed or an acceptablesolvent may for example be water, Ringer's solution and osmotic saline.In addition, an aseptic non-volatile oil can also be employed usually asa solvent or a suspending medium.

For this purpose, any non-volatile oil or fatty acid can be employed,including a naturally-occurring, synthetic or semi-synthetic fatty oilor fatty acid as well as a naturally-occurring, synthetic orsemi-synthetic mono-, di- or triglyceride.

A suppository for a rectal administration of a pharmaceuticalcomposition can be produced by mixing an active ingredient with asuitable non-irritating excipient, such as cacao butter or polyethyleneglycol, which is a solid at ambient temperature but becomes a liquid atthe temperature in the intestinal tract, and then is melted in therectum to release the ingredient.

A solid dosage form for an oral administration of a pharmaceuticalcomposition may for example be powder, granule, tablet, pill and capsuleformulations as described above. In any of such dosage forms, an activeingredient may be mixed with at least one additive such as sucrose,lactose, celluloses, mannitol, maltitol, dextran, starch, agar,alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin,collagen, casein, albumin, synthetic or semi-synthetic polymer orglyceride. Such dosage form may further contain additional customaryadditives such as inert diluent, lubricant such as magnesium stearate,preservative such as paraben or sorbic acid, antioxidant such asascorbic acid, α-tocopherol and cysteine, disintegrant, binder,thickening agent, buffering agent, sweetener, flavorant, perfume and thelike. A tablet and a pill may further be covered with an entericcoating. An oral liquid formulation may also be a pharmaceuticallyacceptable emulsion, syrup, elixir, suspension or solution, which maycontain an inert diluent employed usually in the art such as water.

While the dose of the pharmaceutical composition according to thepresent invention may vary depending on a particular subject, a route ofthe administration and a condition to be treated, a patient having amyocardial infarction (adult weighing about 60 kg) receives usually as asingle dose about 0.005 to about 10 mg/kg, preferably about 0.01 toabout 5 mg/kg, more preferably about 0.2 to about 1 mg/kg (about 0.3 toabout 600 mg/adult, preferably about 0.6 to about 300 mg/adult, morepreferably about 12 to about 60 mg/adult) as(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a salt thereof, which is given preferably about one to about threetimes a day depending on the condition and the like. An acute onset of adisease, such as an acute state after the onset of a myocardialinfarction, may be treated with a higher dose especially at a higherfrequency, for example 4 times a day. Especially in the case of apatient having a myocardial infarction kept in an ICU, a dailyintravenous dose of about 100 mg may be required.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is further described in Reference Examples,Examples, Formulation Examples and Experiments, which are not intendedto restrict the invention. The room temperature in the specificationmeans 0 to 25° C., and each symbol has a meaning described below.

mp: Melting point

s: Singlet

d: Doublet

t: Triplet

dd: Double doublet

ddd: Double double doublet

q: Quartet

m: Multiplet

br: Broad

CDCl₃: Heavy chloroform

CD₃OD: Heavy methanol

DMSO: Dimethyl sulfoxide

DCC: Dicyclohexyl carbodiimide

WSC: Water-soluble carbodiimide

EXAMPLE Reference Example 1

2-Chlorobenzaldehyde (70.3 g) was added to a mixture of acetone (294 ml)and an aqueous solution (1.4 L) of sodium hydroxide (22.0 g) and themixture was stirred at room temperature for 5 hours. An excessiveacetone was distilled off under reduced pressure, and the residue wascombined with ethyl acetate (1.4 L) and extracted. The ethyl acetatelayer was washed with brine and dried (anhydrous magnesium sulfate), andthen ethyl acetate was distilled off under reduced pressure to obtain acrude 2-chlorobenzalacetone (94.6 g) as a yellow oil. This oil wasemployed in the next step without a further purification. A 20% solutionof sodium ethoxide in ethanol (170.1 g) was combined with diethylmalonate (80.1 g) at room temperature (resulting in instantaneousprecipitation), and then with a solution of a crude2-chlorobenzalacetone (94.6 g) in ethanol (40 ml). The reaction mixturewas stirred with heating at 90° C. for 2 hours, allowed to stand tocool, and then cooled on ice (1 hour). The precipitate was recovered bya filtration, washed successively with ethyl acetate and isopropyl etherto obtain a crude6-(2-chlorophenyl)-2-hydroxy-4-oxo-2-cyclohexenene-1-carboxylic acidethyl ester monosodium salt (151.0 g) as a pale yellow powder. Thispowder was combined with 2M sodium hydroxide (350 ml) and stirred withheating at 100° C. for 2 hours. After allowing to stand to cool, 2.5 Msulfuric acid (350 ml) was added over a period of 15 minutes, and themixture was stirred with heating at 100° C. for 2 hours. After allowingto stand to cool, ethyl acetate (1.4 L) was added and extracted. Theethyl acetate layer was washed with brine, dried (anhydrous magnesiumsulfate), and then ethyl acetate was distilled off under reducedpressure. The precipitated crystal was washed successively with ethylacetate-isopropyl ether (1:4) and isopropyl ether to obtain5-(2-chlorophenyl)cyclohexane-1,3-dione (82.1 g) as a colorless crystal.

Mp. 157 to 158° C.

Reference Example 2

A mixture of 5-(2-chlorophenyl)-1,3-cyclohexanedione (1.1 g),1-amino-2-butyne hydrochloride (0.5 g), molecular sieve 4A (2 g) andtetrahydrofuran (20 ml) was combined with triethylamine (0.48 g),stirred at room temperature for 1 hour, and then heated under reflux for12 hours. After cooling, insolubles were filtered off, and the solventwas distilled off under reduced pressure. The residue was stirred at220° C. for 4 hours. Ethyl acetate and aqueous sodium hydrogen carbonatewere added, and the organic layer was washed successively with water andsaturated brine, and then dried over anhydrous magnesium sulfate. Afterconcentrating under reduced pressure, the residue was subjected to acolumn chromatography on a silica gel (EtOAc/hexane) to obtain a crystalwhich was then recrystallized from ethyl acetate-hexane to obtain7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinoline-5-one (0.20 g)as a colorless crystal.

Mp. 97 to 98° C.; ¹H-NMR (CDCl₃) δ: 2.71 (3H, s), 2.84 (1H, dd, J=13, 16Hz), 3.02 (1H, ddd, J=2, 4, 16 Hz), 3.30 (1H, dd, J=12, 17 Hz), 3.48(1H, ddd, J=2, 4, 17 Hz), 3.88-4.07 (1H, m), 7.11 (1H, d, J=5 Hz),7.16-7.34 (4H, m), 8.50 (1H, d, J=5 Hz).

Reference Example 3

A solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.5 g) andammonium acetate (2.6 g) in ethanol (50 ml) was heated under reflux for12 hours. The solvent was distilled off under reduced pressure, andaqueous sodium hydrogen carbonate was added and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the resultant crystal wasrecrystallized from ethyl acetate-hexane to obtain1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.2 g) as a pale yellowcrystal.

Mp. 199° C. (decomposition); ¹H-NMR (CDCl₃) δ: 2.44-2.72 (4H, m),3.77-3.97 (1H, m), 4.68 (2H, br), 5.35 (1H, s), 7.15-7.43 (4H, m).

Reference Example 4

A solution of 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.7 g) inethanol (50 ml) and toluene (150 m) was combined with acetylacetoaldehyde dimethyl acetal (4.0 g) and 85% potassium hydroxide (0.67g), and the mixture was heated under reflux. 85% Potassium hydroxide(0.14 g) was added three times at an interval of 30 minutes, and thenheated under reflux further for 1 hour. The solvent was distilled offunder reduced pressure, and the residue was combined with ethyl acetate,washed successively with water and saturated brine, and dried overmagnesium sulfate. After concentrating under reduced pressure, theresidue was subjected to a column chromatography on a silica gel(EtOAc-hexane) to obtain7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.5 g) asa crystal. Melting point and NMR data were in agreement with those ofthe compound obtained in Reference Example 2.

Example 1 (Production of Compound A)

A mixture of7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolein-5-one (0.20 g),aminoguanidine hydrochloride (0.085 g), concentrated hydrochloric acid(0.11 ml), water (0.11 ml) and ethanol (20 ml) was heated under refluxfor 6 hours. The solvent was distilled off under reduced pressure, andthe residue was dissolved in water, washed with ethyl acetate, andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-ethanol to obtain7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (Compound A) (0.21 g) as a colorless crystal.

Mp. 204° C. (decomposition); Calculated as C₁₇H₁₈N₅Cl.2HCl.0.8H₂O: C,49.18; H, 5.24; N, 16.87; Found C, 49.46; H. 5.10; N, 16.88; ¹H-NMR(DMSO-d₆) δ: 2.65-3.00 (1H, m), 2.88 (3H, s), 3.15-3.78 (4H, m), 7.2-8.2(4H, br), 7.28-7.53 (3H, m), 7.58-7.66 (1H, m), 7.83 (1H, d, J=6 Hz),8.63 (1H, d, J=6 Hz), 11.45 (1H, s).

Example 2 (Production of Compound B)

(±)-7-(2-Chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (123.9 g) was suspended in methanol (1200 ml) and treateddropwise with a 28% solution of sodium methoxide in methanol (119.2 ml).The mixture was stirred at 50° C. for 30 minutes. The solvent wasdistilled off under reduced pressure, and the residue was combined withwater and then the crystal was recovered by a filtration. The crystalwas washed with water and dried to obtain(±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(109.3 g) as a colorless crystal. To a solution of(±)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(109.3 g) in isopropyl alcohol (700 ml), a solution of L-pyroglutamicacid (10 g) in isopropyl alcohol (150 m) was added dropwise at 50° C.over a period of 1.5 hours. The mixture was stirred at 50° C. for 1 hourand then at room temperature for 2 days. The crystal was recovered by afiltration and washed with isopropyl alcohol to obtain(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineL-pyroglutamate (55.5 g, 88% ee). A recrystallization from ethanolresulted in an L-pyroglutamate (44.3 g, 97% ee). The crystal of the saltthus obtained was suspended in methanol (500 ml) and combined with a 28%methanol solution of sodium methoxide (10.9 ml). The mixture was stirredat 50° C. for 30 minutes and then the solvent was distilled off underreduced pressure. The crystal obtained was washed with water and driedto obtain(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(38.9 g). (This compound was proven to have an absolute configuration ofan S form based in an X-ray crystal structure analysis.)

The product thus obtained was dissolved in ethanol (400 ml) and combinedwith methanesulfonic acid (21.1 g). The solvent was distilled off underreduced pressure and the resultant crystal was recrystallized fromethanol to obtain(−)-7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinemethanesulfonate (Compound B) (46.8 g, 99.2% ee).

Mp. 194 to 195° C.; [α]_(D)−56.9° (c=1, MeOH); Calculated asC₁₇H₁₈N₅Cl.2MeSO₃H: C, 43.88; H, 5.04; N, 13.47; Cl, 6.82; Found C,43.67; H, 4.90; N, 13.18; Cl, 6.76; ¹H-NMR (DMSO-d₆) δ: 2.40 (6H, s),2.78 (1H, dd, J=12, 18 Hz), 2.89 (3H, s), 3.08-3.32 (2H, m), 3.44-3.80(2H, m), 7.2-8.1 (4H, br), 7.31-7.56 (3H, m), 7.58-7.66 (1H, m), 7.86(1H, d, J=6 Hz), 8.66 (1H, d, J=6 Hz), 10.77 (1H, s).

Reference Example 5

A solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydroustetrahydrofuran was treated dropwise at −78° C. with a 1.6 M solution ofbutyllithium in hexane (55.5 ml). At the same temperature, the mixturewas stirred and treated dropwise with a solution of dimethylformamide(6.8 g) in tetrahydrofuran (20 ml). After being allowed to warm to 0°C., the reaction mixture was combined with ice-water. The reactionmixture was extracted with ethyl acetate, and the organic layer waswashed successively with water and saturated brine, and then dried overmagnesium sulfate. The solvent was distilled off under reduced pressureto obtain 5-fluoro-2-methylbenzaldehyde (11.5 g) as an oil.

A mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100ml) was treated at room temperature dropwise with a solution of5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml) and stirred atthe same temperature for 1 hour. Acetone was distilled off under reducedpressure, and the mixture was extracted with ethyl acetate. The organiclayer was washed successively with water and saturated brine andconcentrated under reduced pressure to obtain4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g).

A 20% solution of sodium ethoxide in ethanol (29.7 g) was combined at 0Cwith diethyl malonate (14.0 g) and then with4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g) in portions. Thereaction mixture was stirred at room temperature for 30 minutes, andthen stirred with heating for 2 hours. After allowing to stand to cool,the solvent was distilled off, and the residue was combined with waterand the aqueous layer was washed with ethyl acetate and thenconcentrated. 2M Sodium hydroxide (46 ml) was added and the mixture washeated under reflux for 1 hour. After allowing to stand to cool, 2.5Msulfuric acid (46 ml) was added over 10 minutes, and the mixture washeated under reflux for 30 minutes. After allowing to stand to cool, theprecipitated crystal was recovered by a filtration and washedsuccessively with water and isopropyl ether to obtain5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (8.6 g) as a colorlesscrystal.

Mp. 175 to 176° C.; ¹H-NMR (CDCl₃) δ: 2.30 (3H, s), 2.27-2.56 (4H, m),2.5-4.3 (1H, br), 3.44-3.63 (1H, m), 5.55 (1H, s), 6.77-7.01 (2H, m),7.09-7.17 (1H, m).

Reference Example 6

A solution of 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (3.0 g)and ammonium acetate (3.1 g) in ethanol (50 ml) was heated under refluxfor 14 hours. The solvent was distilled off under reduced pressure, andthe residue was dissolved in ethyl acetate, washed successively withwater and saturated brine and then dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain1-amino-5-(5-fluoro-2-methylphenyl)cyclohexen-3-one. This was dissolvedin ethanol (70 ml) and toluene (120 ml), combined with3-oxobutylaldehyde dimethyl acetal (4.1 g) and potassium hydroxidepowder (0.57 g), and then heated under reflux. The mixture was combinedwith potassium hydroxide powder (0.12 g) after 30 minutes and withpotassium hydroxide powder (0.12 g) and 3-oxobutylaldehydedimethylacetal (0.33 g) after 1 hour and further with potassiumhydroxide powder (0.12 g) after 1 hour and 30 minutes, and then stirredat the same temperature for 2 hours. After cooling, the solvent wasdistilled off under reduced pressure, and ethyl acetate was added. Theorganic layer was washed successively with water and saturated brine,and dried over magnesium sulfate. Ethyl acetate was distilled off underreduced pressure, and the residue was subjected to a silica gel column(ethyl acetate-hexane) to obtain a crystal which was then recrystallizedfrom ethyl acetate-hexane to obtain7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one(1.5 g).

Mp. 113 to 114° C.; ¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 2.71 (3H, s),2.78-2.98 (2H, m), 3.24 (1H, dd, J=11, 16 Hz), 3.28-3.44 (1H, m),3.55-3.74 (1H, m), 6.82-7.04 (2H, m), 7.12 (1H, d, J=5 Hz), 7.07-7.22(2H, m), 8.50 (1H, d, J=5 Hz).

Example 3 (Production of Compound C)

A solution of7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one(1.1 g) and aminoguanidine hydrochloride (0.54 g) in ethanol (30 ml) wascombined with concentrated hydrochloric acid (1.0 ml) and water (1.0 ml)and heated under reflux for 6 hours. The solvent was distilled off underreduced pressure, and the residue was dissolved in water and washed withethyl acetate. The aqueous layer was made alkaline with aqueous sodiumhydrogen carbonate and extracted with ethyl acetate. The organic layerwas washed successively with water and saturated brine, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas dissolved in ethanol, combined with 1N hydrochloric acid (10 ml) andconcentrated, and then the precipitated crystal was recrystallized fromethanol to obtain7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (Compound C) (1.4 g) as a colorless crystal.

Mp. 202 to 205° C.; Calculated as C₁₈H₂₀N₅F.2HCl.0.5H₂O: C, 53.08; H,5.69; N, 17.19; Found C, 53.33; H, 5.87; N, 16.94; ¹H-NMR (DMSO-d₆) δ:2.31 (3H, s), 2.72-3.03 (1H, m), 2.90 (3H, s), 3.13-3.57 (4H, m),6.93-7.06 (1H, m), 7.17-7.4 (2H, m), 7.5-8.4 (4H, br), 7.85 (1H, d, J=6Hz), 8.65 (1H, d, J=6 Hz), 11.39 (1H, s).

Example 4 (Production of Compounds D, E and F)

(±)-7-(5-Fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (43.8 g) was suspended in methanol (300 ml), and treateddropwise with a 28% solution of sodium methoxide in methanol (53.1 g).The mixture was concentrated under reduced pressure, and the residue waswashed with water and dried to obtain(±)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(33.0 g).

A solution of(±)-7-(5-Fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(2.0 g) in ethanol (25 ml) was combined with D-pyroglutamic acid (0.79g) at 80° C. to form a uniform solution. The solution was allowed towarm to room temperature gradually, and then stirred at the sametemperature for 14 hours. The precipitated crystal was recovered by afiltration and recrystallized from ethanol to obtain(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineD-pyrglutamate (1.2 g). This crystal was suspended in methanol (20 ml)and combined with a 28% solution of sodium methoxide in methanol (0.24g), and then the solvent was distilled off under reduced pressure. Theresultant crystal was washed with water and dried to obtain a free form(0.43 g). This was dissolved in ethanol (15 ml) and combined withmethanesulfonic acid (0.24 g). The solvent was distilled off underreduced pressure and the resultant crystal was recrystallized fromethanol to obtain(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinemethanesulfonate (Compound D) (0.5 g, 99.7% ee).

Mp. 202 to 204° C. [α]_(D)−61.4° (c=1, MeOH); Calculated asC₁₈H₂₀FN₅.2MeSO₃H: C, 46.41; H, 5.45; N, 13.51; Found C, 46.28; H, 5.30;N, 13.51; ¹H-NMR (DMSO-d₆) δ: 2.30 (3H, s), 2.35 (6H, s), 2.62-2.95 (1H,m), 2.86 (3H, s), 2.99-3.24 (2H, m), 3.3-3.6 (2H, m), 6.96-7.11 (1H, m),7.19-7.42 (2H, m), 7.7 (4H, br), 7.81 (1H, d, J=5 Hz), 8.65 (1H, d, J=5Hz), 10.68 (1H, s).

A solution of(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(1.5 g) in ethanol (20 ml) was combined with concentrated hydrochloricacid (1.2 ml) and concentrated. The resultant crystal was recrystallizedfrom a solvent mixture of ethanol and water to obtain(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (Compound E) (0.96 g, 99.3% ee). (This compound was provento have an absolute configuration of an S form based in an X-ray crystalstructure analysis.)

Mp. 192 to 198° C.; Calculated as C₁₈H₂₀FN₅.2HCl1H₂O: C, 51.93; H, 5.81;N, 16.82; Found C, 51.94; H, 5.84; N, 16.74; ¹H-NMR (DMSO-d₆) δ: 2.31(3H, s), 2.66-3.03 (1H, m), 2.89 (3H, s), 3.12-3.6 (4H, m), 6.94-7.06(1H, m), 7.16-7.37 (2H, m), 7.4-8.3 (4H, br) 7.85 (1H, d, J=6 Hz), 8.64(1H, d, J=6 Hz), 11.41 (1H, s).

A mother liquor and washings which had been resolved with D-pyroglutamicacid were combined with a 28% solution of sodium methoxide in methanol(0.22 g), concentrated and washed with water to obtain a (+)-isomer-richcrystal (1.1 g). This was dissolved in ethanol (10 ml) and combined withL-pyroglutamic acid (0.42 g) at 80° C. to form a uniform solution. Thesolution was allowed to warm to room temperature gradually, and themixture was stirred at room temperature for 14 hours. The precipitatedcrystal was recovered by a filtration, washed with ethanol to obtain(+)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineL-pyroglutamate (1.1 g). This crystal was suspended in methanol (15 ml)and combined with a 28% solution of sodium methoxide in methanol (0.47g) and the solvent was distilled off under reduced pressure. The residuewas washed with water and dried to obtain a free form (0.77 g). This wasdissolved in ethanol (20 ml) and combined with methanesulfonic acid(0.47 g). The solvent was distilled off under reduced pressure and theresultant crystal was recrystallized from ethanol to obtain(+)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinemethanesulfonate (Compound F) (1.1 g, 99.4% ee).

Mp. 202 to 204° C.; [α]_(D)+60.5° (c=1, MeOH); Calculated asC₁₈H₂₀FN₅.2MeSO₃H: C, 46.41; H, 5.45; N, 13.51; Found C, 46.27; H, 5.30;N, 13.48; ¹H-NMR (DMSO-d₆) was in agreement with that of Compound D.

Example 5 (Production of Compound G)

A solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40ml) was treated dropwise with concentrated sulfuric acid (40 ml) withcooling on ice. Subsequently, a solution of chromic anhydride (9.3 g) inacetic anhydride (40 ml) was added dropwise over a period of 2 hours. Atthe same temperature, the mixture was stirred for 1 hour, and added toan ice-water. The mixture was extracted with diethyl ether and theorganic layer was washed successively with aqueous sodium carbonate,water and saturated brine, and then dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the residue wasdissolved in tetrahydrofuran (10 ml), combined with water (4 ml) andconcentrated sulfuric acid (4 ml), and heated with stirring at 100° C.for 30 minutes. After allowed to stand to cool, the reaction mixture wasextracted with ethyl acetate, and the organic layer was washedsuccessively with aqueous sodium carbonate, water and saturated brine,and dried over magnesium sulfate. The solvent was distilled off and theresidue was subjected to a column chromatography on a silica gel toobtain 2-chloro-5-fluorobenzaldehyde (1.6 g).

The same reaction was repeated to obtain 2-chloro-5-fluorobenzaldehyde(1.2 g).

Sodium hydroxide (0.78 g) was dissolved in water (55 ml) and treateddropwise with acetone (55 ml) followed by a solution of2-chloro-5-fluorobenzaldehyde (2.8 g) in acetone (10 ml). The reactionmixture was stirred at room temperature for 2 hours. Acetone wasdistilled off under reduced pressure, and the residue was extracted withethyl acetate. The organic layer was washed successively with water andsaturated brine, and concentrated under reduced 5 pressure to obtain4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g).

A 20% solution of sodium ethoxide in ethanol (0.43 g) was combined atroom temperature with diethyl malonate (0.2 g) followed by4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g) in portions at 0C.The reaction mixture was stirred at room temperature for 30 minutes andheated under reflux for 2 hours. After allowing to stand to cool, thesolvent was distilled off, and the residue was dissolved in water andthe aqueous layer was washed with ethyl acetate and concentrated. 2Msodium hydroxide (0.7 ml) was added and the mixture was heated underreflux for 2 hours. After allowing to stand to cool, 2.5 M sulfuric acid(0.7 ml) was added, and the mixture was heated under reflux for 15minutes. The mixture was extracted with ethyl acetate, and the organiclayer was washed successively with water and saturated brine. Afterdrying over magnesium sulfate followed by distilling the solvent offunder reduced pressure, 5-(2-chloro-5-fluorophenyl)cyclohexane-1,3-dione(0.17 g) as an oil.

A solution of 5-(2-chloro-5-fluorophenyl)cyclohexane-1,3-dione (0.17 g)and ammonium acetate (0.16 g) in ethanol (10 ml) was heated under refluxfor 12 hours. The solvent was distilled off under reduced pressure, andthe residue was combined with ethyl acetate and then the organic layerwas washed successively with aqueous sodium carbonate, water andsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was dissolved inethanol (3.5 ml) and toluene (6 ml), combined with 3-oxobutylaldehydedimethyl acetal (0.21 g) and potassium hydroxide powder (34 mg) and thenheated under reflux. The mixture was combined with potassium hydroxidepowder (7 mg) after 30 minutes and with potassium hydroxide powder (7mg) and 3-oxobutylaldehyde dimethyl acetal (17 mg) after 1 hour andfurther with potassium hydroxide powder (7 mg) after 1 hour and 30minutes, and then stirred at the same temperature for 2 hours. Aftercooling, the solvent was distilled off under reduced pressure, and thenthe mixture was extracted with ethyl acetate. The organic layer waswashed successively with water and saturated brine, and dried overmagnesium sulfate. Ethyl acetate was distilled off under reducedpressure, and the residue was subjected to a column chromatography on asilica gel (ethyl acetate-hexane) to obtain7-(2-chloro-5-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one.

A solution of7-(2-chloro-5-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one inethanol (10 ml) was combined with aminoguanidine hydrochloride (0.041g), concentrated hydrochloric acid (0.078 ml) and water (0.078 ml), andthe mixture was heated under reflux for 4 hours. The solvent wasdistilled off under reduced pressure, and the residue was combined withwater and the aqueous layer was washed with ethyl acetate. The aqueouslayer was made alkaline with aqueous sodium hydrogen carbonate andextracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved in 1Nhydrochloric acid (1 ml) and concentrated. The resultant crystal wasrecrystallized from ethanol-ethyl acetate to obtain7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (Compound G) (0.05 g) as a colorless crystal.

Mp. 268° C. (decomposition); ¹H-NMR (DMSO-d₆) δ: 2.76-3.05 (1H, m), 2.84(3H, s), 3.13-3.75 (4H, m), 7.0-8.4 (4H, br), 7.2-7.34 (1H, m),7.52-7.66 (2H, m), 7.76 (1H, d, J=6 Hz), 8.6 (1H, d, J=6 Hz), 11.36 (1H,s).

Example 6 (Production of Compound H, I and J)

(±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (8.8 g) was suspended in methanol (100 ml) and treateddropwise with a 28% solution of sodium methoxide in methanol (8.9 g) Themixture was concentrated under reduced pressure, and the result waswashed with water and dried to obtain(±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(7.1 g).

A solution of(±)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(7.1 g) in ethanol (85 ml) was combined with L-pyroglutamic acid (2.72g) and heated to form a uniform solution. The mixture was allowed tostand to cool gradually, and stirred at room temperature for 14 hours.The crystal precipitated was recovered by a filtration and washed withethanol to obtain(+)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineL-pyroglutamate (4.1 g). This crystal was suspended in methanol (50 ml)and combined with a 28% solution of sodium methoxide in methanol (1.7 g)and then the solvent was distilled off under reduced pressure. Theresultant crystal was washed with water and dried to obtain a crystal(3.1 g). This was dissolved in ethanol (20 ml) and combined withmethanesulfonic acid (1.8 g). The solvent was distilled off underreduced pressure, and the resultant crystal was recrystallized fromethanol to obtain(+)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinemethanesulfonate (Compound H)(3.6 g, 99.3% ee).

Mp. 209 to 212° C.; [α]_(D)+57.2° (c=1, MeOH); Calculated asC₁₇H₁₇ClFN₅.2MeSO₃H: C, 42.42; H, 4.68; N, 13.02; Found C, 42.43; H,4.68; N, 13.13; ¹H-NMR (DMSO-d₆) δ: 2.43 (6H, s), 2.73-2.92 (1H, m),2.90 (3H, s), 3.06-3.31 (2H, m), 3.37-3.79 (2H, m), 7.0-8.6 (4H, br),7.14-7.26 (1H, m), 7.48-7.62 (2H, m), 7.85 (1H, d, J=6 Hz), 8.68 (1H, d,J=6 Hz), 10.86 (1H, s).

A mother liquor and washings which had been resolved with L-pyroglutamicacid were combined with a 28% solution of sodium methoxide in methanol(2.6 g), concentrated and washed with water to obtain a (−)-isomer-richcrystal (3.7 g). This was dissolved in ethanol (30 ml) and combined witha solution of D-pyroglutamic acid (1.4 g) in ethanol (10 ml) at 80° C.The solution was allowed to warm to room temperature gradually, and themixture was stirred at room temperature for 14 hours. The precipitatedcrystal was recovered by a filtration, washed with ethanol to obtain(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineD-pyroglutamate (4.0 g). This crystal was suspended in methanol (40 ml)and combined with a 28% solution of sodium methoxide in methanol (1.6 g)and the solvent was distilled off under reduced pressure. The residuewas washed with water and dried to obtain(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(2.9 g).(−)-7-(2-Chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(1.7 g) was dissolved in ethanol (30 ml) and combined withmethanesulfonic acid (0.97 g). The solvent was distilled off underreduced pressure and the resultant crystal was recrystallized fromethanol to obtain(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinemethanesulfonate (Compound I) (2.3 g, 99.5% ee).

Mp. 206 to 209° C.; [α]_(D)−58.2° (c=1, MeOH); Calculated asC₁₇H₁₇ClFN₅.2MeSO₃H: C, 42.42; H, 4.68; N, 13.02; Found C, 42.34; H,4.67; N, 13.06; ¹H-NMR (DMSO-d₆) was in agreement with that of CompoundH.

A solution of(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline(1.2 g) in ethanol (20 ml) was combined with concentrated hydrochloricacid (0.76 ml) and concentrated. The resultant crystal wasrecrystallized from a solvent mixture of ethanol and water to obtain(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (Compound J) (1.3 g, 99.4% ee). (This compound was provento have an absolute configuration of an S form based in an X-ray crystalstructure analysis.)

Mp. 194 to 197° C.; [α]_(D)−71.2° (c=1, MeOH); Calculated asC₁₈H₂₀FN₅.2HCl.0.5H₂O: C, 47.74; H, 4.71; N, 16.37; Found C, 47.56; H,4.97; N, 16.56; ¹H-NMR (DMSO-d₆) δ: 2.75-3.02 (1H, m), 2.90 (3H, s),3.15-3.32 (1H, m), 3.36-3.83 (2H, m), 6.13-7.28 (1H, m), 7.48-7.60 (2H,m), 7.92 (4H, br), 7.85 (1H, d, J=6 Hz), 8.65 (1H, d, J=6 Hz), 11.53(1H, s).

Reference Example 7

A mixture of acetone (45 ml), sodium hydroxide (3.1 g) and water (230ml) was combined at room temperature with a solution of2,5-difluorobenzaldehyde (10.0 g) in acetone (10 ml) and stirred at thesame temperature for 30 minutes. Acetone was distilled off under reducedpressure and extracted with ethyl acetate. The organic layer was washedsuccessively with water and saturated brine and concentrated underreduced pressure to obtain 4-(2,5-difluorophenyl)-3-buten-2-one (13.8g).

A 20% solution of sodium ethoxide in ethanol (27.7 g) was combined atroom temperature with diethyl malonate (13.0 g) and then with4-(2,5-difluorophenyl)-3-buten-2-one (13.8 g) in portions. The reactionmixture was stirred at room temperature for 30 minutes and then heatedwith stirring for 2 hours. After allowing to stand to cool, the solventwas distilled off, and the residue was combined with water, and theaqueous layer was washed with ethyl acetate and concentrated. 2N Sodiumhydroxide (42 ml) was added and the mixture was heated under reflux for2 hours. After allowing to stand to cool, 2.5 M sulfuric acid (42 ml)was added over a period of 10 minutes, and then the mixture was heatedunder reflux for 3 hours. After allowing to stand to cool, theprecipitated crystal was recovered by a filtration and washedsuccessively with water and isopropyl ether to obtain5-(2,5-difluorophenyl)cyclohexane-1,3-dione (11.6 g) as a colorlesscrystal.

Mp. 176° C. (decomposition); ¹H-NMR (DMSO-d₆) δ: 2.0-3.0 (4H, m),3.43-3.64 (1H, m), 5.31 (1H, s), 7.04-7.37 (4H, m), 11.26 (1H, br).

Reference Example 8

A solution of 5-(2,5-difluorophenyl)cyclohexane-1,3-dione (4.0 g) andammonium acetate (4.1 g) in ethanol (60 ml) was heated under reflux for12 hours. The reaction mixture was concentrated under reduced pressure,and the residue was washed with water and dried to obtain1-amino-5-(2,5-difluorophenyl)cyclohexan-3-one (3.7 g).

A mixture of 1-amino-5-(2,5-difluorophenyl)cyclohexan-3-one (3.7 g),3-oxobutylaldehyde dimethyl acetal (5.5 g), toluene (120 ml) and ethanol(70 ml) was stirred at 115° C. with adding potassium hydroxide powder(0.77 g). The mixture was combined with potassium hydroxide powder (0.16g) after 30 minutes and with potassium hydroxide powder (0.16 g) and3-oxobutylaldehyde dimethyl acetal (0.44 g) after 1 hour and furtherwith potassium hydroxide powder (0.16 g) after 1 hour and 30 minutes,and then stirred at the same temperature for 5 hours. After cooling, thesolvent was distilled off under reduced pressure and ethyl acetate wasadded. The organic layer was washed successively with water andsaturated brine, and dried over magnesium sulfate. Ethyl acetate wasdistilled off under reduced pressure, and the residue was subjected to asilica gel column (ethyl acetate-hexane), and the resultant crystal wasrecrystallized from ethyl acetate-hexane to obtain7-(2,5-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.3g).

Mp. 75 to 76° C.; ¹H-NMR (CDCl₃) δ: 2.70 (3H, s), 2.86 (1H, dd, J=12, 16Hz), 2.99 (1H, ddd, J=2, 5, 16 Hz), 3.33 (1H, dd, J=11, 17 Hz),3.37-3.53 (1H, m), 3.66-3.89 (1H, m), 6.88-7.24 (3H, m), 7.11 (1H, d,J=5 Hz), 8.50 (1H, d, J=5 Hz).

Example 7 (Production of Compound K)

A solution of7-(2,5-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.2 g)and aminoguanidine hydrochloride (0.58 g) in ethanol (30 ml) wascombined with concentrated hydrochloric acid (1.1 ml) and water (1.1ml), and the mixture was heated under reflux for 14 hours. The solventwas distilled off under reduced pressure, and the resultant crystal wasrecrystallized from ethanol to obtain7-(2,5-difluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolinehydrochloride (Compound K) (1.6 g) as a colorless crystal.

mp. 290° C. (decomposition); ¹H-NMR (DMSO-d₆) δ: 2.6-3.03 (1H, m), 2.87(3H, s), 3.14-3.72 (4H, m), 7.12-7.38 (2H, m), 7.42-7.56 (1H, m),7.6-8.4 (4H, br), 7.83 (1H, d, J=6 Hz), 8.64 (1H, d, J=6 Hz), 11.58 (1H,s).

Reference Example 9

A mixture of 5-(5-fluoro-2-methylphenyl)-cyclohexane-1,3-dione (1.5 g)and ammonium acetate (1.6 g) in butanol(30 ml) was combined withacetylacetone (2.0 g) and heated under reflux for 3 days. The solventwas distilled off under reduced pressure, and the residue was dissolvedin ethyl acetate, washed successively with aqueous sodium hydrogencarbonate, water and saturated brine, and dried over magnesium sulfate.The mixture was concentrated under reduced pressure, and the residue wassubjected to a column chromatography on a silica gel (ethylacetate-hexane) to obtain7-(5-fluoro-2-methylphenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one(1.2 g) as an oil.

¹H-NMR (CDCl₃) δ: 2.32 (3H, s), 2.54 (3H, s), 2.67 (3H, s), 2.75-3.0(2H, m), 3.12-3.43 (H, m), 3.54-3.78 (1H, m), 6.92 (1H, s), 6.82-7.09(3H, m), 7.10-7.23 (1H, m).

Example 8 (Production of Compound L)

A solution of7-(5-fluoro-2-methylphenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one(1.1 g) and aminoguanidine hydrochloride (0.52 g) in ethanol (30 ml) wascombined with concentrated hydrochloric acid (1.0 ml) and water (1.0ml), and the mixture was heated under reflux for 12 hours. The mixturewas concentrated under reduced pressure, and the residue wasrecrystallized from ethanol to obtain7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinolinehydrochloride (Compound L) (1.25 g) as a colorless crystal.

Mp. 201 to 203° C.; ¹H-NMR (DMSO-d₆) δ: 2.3 (3H, s), 2.6-3.0 (1H, m),2.72 (3H, s), 2.83 (3H, s), 3.0-4.0 (4H, m), 6.97-7.12 (1H, m),7.18-7.45 (2H, m), 7.5-8.4 (4H, br), 7.72 (1H, s), 11.32 (1H, s).

Formulation Example 1

70 mg of Compound B synthesized in Example 2 was dissolved in 7 ml ofdistilled water. 0.5 ml of this solution was added to 195 mg of calciumcarbonate (mean particle size: 38 μm) and combined further with 0.5 mlof distilled water, and freeze-dried to obtain a powder, which was thenmixed in a mortar to obtain a pharmaceutical preparation.

Formulation Example 2

33 mg of Compound B synthesized in Example 2 was dissolved in 3.3 ml ofdistilled water. 1 ml of this solution was added to 190 mg of calciumcarbonate (mean particle size: 38 μm) and freeze-dried to obtain apowder, which was then mixed in a mortar to obtain a pharmaceuticalpreparation.

Formulation Example 3

33 mg of Compound B synthesized in Example 2 was dissolved in 3.3 ml ofdistilled water. 2 ml of this solution was added to 180 mg of calciumcarbonate (mean particle size: 38 μm) and freeze-dried to obtain apowder, which was then mixed in a mortar to obtain a pharmaceuticalpreparation.

Formulation Example 4

70 mg of Compound B synthesized in Example 2 was dissolved in 7 ml ofdistilled water. 6 ml of this solution was added to 240 mg of calciumcarbonate (mean particle size: 38 μm) and freeze-dried to obtain apowder, which was then mixed in a mortar to obtain a pharmaceuticalpreparation.

Formulation Example 5

12.5 mg of Compound B synthesized in Example 2 was dissolved in 0.5 mlof a 5% aqueous solution of mannitol to obtain a pharmaceuticalpreparation in the form of a solution.

Formulation Example 6

25 mg of Compound B synthesized in Example 2 was dissolved in 0.5 ml ofa 5% aqueous solution of mannitol to obtain a pharmaceutical preparationin the form of a solution.

Formulation Example 7

30 mg of Compound B synthesized in Example 2 was dissolved in 3 ml ofdistilled water. 2 ml of this solution was added to 180 mg ofhydroxyapatite (TAIHEIKAGAKU SANGYO, HAP100) and freeze-dried to obtaina powder, which was then mixed in a mortar to obtain a pharmaceuticalpreparation.

Formulation Example 8

30 mg of Compound B synthesized in Example 2 was dissolved in 3 ml ofdistilled water. 2 ml of this solution was added to 180 mg ofcrystalline cellulose (ASAHI KASEI KOGYO, AVICEL) and freeze-dried toobtain a powder, which was then mixed in a mortar to obtain apharmaceutical preparation.

Formulation Example 9

30 mg of Compound B synthesized in Example 2 was dissolved in 3 ml ofdistilled water. 2 ml of this solution was added to 180 mg ofhydroxypropyl cellulose (NIPPON SODA) and freeze-dried to obtain apowder, which was then mixed in a mortar to obtain a pharmaceuticalpreparation.

Comparative 1

9 mg of Compound B synthesized in Example 2 was dissolved in 4.5 ml of a5% aqueous solution of mannitol to obtain a pharmaceutical preparationin the form of a solution.

Experiment 1

(Method)

A male SD rat (8 weeks old) was anesthetized with ether and each of thepreparations of Formulation Examples 1 to 6 was given into the leftnasal cavity. The dose of Compound B was 0.75 mg/kg (Formulation Example1), 1.5 mg/kg (Formulation Example 2), 3.0 mg/kg (Formulation Example3), 6.0 mg/kg (Formulation Example 4), 1.5 mg/kg (Formulation Example 5)and 3.0 mg/kg (Formulation Example 6). Each of the preparations ofFormulation Examples 1 to 4 was taken as a portion of about 10 mg, whichwas filled in a polyethylene tube (INTRAMEDIC PE90, BECKTON DICKINSON)and the polyethylene tube was inserted into the nasal cavity, where itwas sprayed with 2 cc of air. Each of the preparations of FormulationExamples 5 and 6 was given as a 20 μl aliquot via a micropipette(*EXCELMYDEGI* 8000, D-5, SANKO JUNYAKU). The preparation of Comparative1 was given intravenously into a femoral vein of the rat (dose: 1mg/kg).

After administration of the preparation, blood was taken at a certaininterval via a tail vain and examined for the serum concentration ofCompound B.

(Results)

The change in the serum concentration of Compound B is shown in FIG. 1and FIG. 2. Each preparation of Formulation Examples 1 to 4, 5 and 6according to the present invention, after given nasally, exhibited thechange similar to that observed after an intravenous administration.Accordingly, a nasal administration was proven to enable a rapid in vivoabsorption of Compound B.

Experiment 2

(Method)

The efficacy of Compound B was evaluated in a myocardial infarctionmodel employing occlusion and re-perfusion of a rat coronary arterydescribed below.

A male Wistar rat (11 weeks old) was anesthetized with pentobarbital andsubjected to a thoracolaparotomy under an artificial respiration. Apericardium was opened to expose the heart, and threaded at the basilarregion of the left coronary artery together with the myocardium. About5.3 mg of the preparation of Formulation Example 3 (1.5 mg/kg asCompound B) was given to the left nasal cavity similarly toExperiment 1. Compound B was dissolved at 2 mg/ml in 0.5% methylcellulose to obtain a reference control, which was given orally at 5ml/kg (10 mg/kg as Compound B). The coronary artery was occluded 5minutes after nasal administration or 1 hour after oral administration.The thread was loosened after 1 hour, and the blood flow was restoredand the chest was closed. The animal was returned to the cage as beingconscious, and housed until the next day. After 24 hours, the animal wasanesthetized again with pentobarbital, received heparin (1000 U/kg)intravenously and then the heart was taken out. The aorta received aretrograde insertion of a polyethylene tube and the heart was made freeof any excessive blood using physiological saline. The thread remainingin the myocardium was ligated again and 1% Evans blue was perfused tostain a normal region, whereby determining the ischemic region.Subsequently, the left ventricle was divided into 6 equal portions inparallel with the vertical axis, which were exposed to 1%triphenyltetrazolium chloride at 37° C. for 10 minutes to stainnon-necrosis cell, whereby weighing an infarction focus.

(Results)

Each infarction focus was represented as % by weight per ischemicregion. The results of Formulation Example 3 or a reference control wererepresented also by % based on % by weight of the infarction focus perischemic region after nasal administration only of calcium carbonate orafter oral administration only of 0.5% methyl cellulose being regardedas 100. It is evident that the nasal preparation exhibited a highmyocardial infarction focus reducing effect when compared with the oraladministration in spite of a lower dose.

TABLE 1 Infarction weight/ischemic region (%) (%) Calcium carbonate 55.3100 Formulation Example 3 31.4 56.8 0.5% Methyl cellulose 60.3 100Reference control 41.1 68.2

INDUSTRIAL APPLICABILITY

Since the nasal preparation according to the present invention exhibitsan excellent in vivo absorption performance and has an Na—H exchangeinhibitory activity which is more excellent than that of an oralpreparation, it is useful as a prophylactic and therapeutic agentagainst an ischemic heart disease such as myocardial infarction andarrhythmia.

What is claimed is: 1.(S)-(−)-7-(5-Fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof. 2.(S)-(−)-7-(2-Chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof.
 3. A composition comprising(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof; or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof and a pharmaceutically acceptablecarrier.
 4. A method for inhibiting Na—H exchange in mammals comprisingadministering an effective amount of(S)-(−)-7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof; or(S)-(−)-7-(2-chloro-5-fluorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinolineor a prodrug or a salt thereof to said mammals.